N-[(3-heteroaryl-1-pyrrolidinyl)-alkyl]phthalimides and related compounds and their therapeutic utility

ABSTRACT

Heteroarylpiperidines, pyrrolidines, and piperazines are useful as antipsychotic and analgesic agents. the compounds are especially useful for treating psychoses by administering to a mammal a psychoses-treating effective amount of one of the compounds. Depot derivatives of the compounds are useful for providing long acting effects of the compounds. The compounds are also useful as analgesics by administering a pain-relieving effective amount of one of the compounds to a mammal.

CROSS-REFERENCE TO RELATED APPLICATION

This is a division of pending application Ser. No. 08/329,000 filed Oct.25, 1994 of Joseph T. Strupczewski, Grover C. Helsley, Edward J.Glamkowski, Yulin Chiang, Kenneth J. Bordeau, Peter A. Nemoto and JohnJ. Tegeler for HETEROARYLPIPERIDINES, PYRROLIDINES AND PIPERAZINES ANDTHEIR USE AS ANTIPSYCHOTICS AND ANALGETICS, U.S. Pat. No. 5,776,963,which is a continuation-in-part application of Ser. No. 08/144,265,filed Oct. 28, 1993, now abandoned, which is a continuation-in-partapplication of Ser. No. 07/969,383, filed Oct. 30, 1992, now U.S. Pat.No. 5,364,866 which is a continuation-in-part application of Ser. No.07/788,269, filed Nov. 5, 1991, now abandoned, which is acontinuation-in-part application of Ser. No. 07/944,705, filed Sep. 5,1991, now abandoned, which is a continuation application of Ser. No.07/619,825, filed Nov. 29, 1990, now abandoned, which is a continuationapplication of Ser. No. 07/456,790, filed Dec. 29, 1989, now abandoned,which is a continuation-in-part application of Ser. No. 07/354,411,filed May 19, 1989, now abandoned. The entire disclosure of theseapplications is relied upon and incorporated by reference herein.

BACKGROUND OF THE INVENTION

This invention relates to heteroarylpiperidines, pyrrolidines andpiperazines. More particularly, this invention relates toheteroarylpiperidines, pyrrolidines and piperazines having antipsychoticactivity and to their use as antipsychotic drugs.

The therapeutic treatment of schizophrenic patients by administration ofneuroleptic drugs, such as chlorpromazine, haloperidol, sulpiride, andchemically closely related compounds, is widespread. While control ofschizophrenic symptoms has been successful, treatment with these drugsdoes not cure the psychotic patient, who will almost certainly relapseif medication is discontinued. There exists a continuing need in the artfor antipsychotic drugs for the treatment of psychoses.

Moreover, some of the known neuroleptics produce unwanted side effects.For example, the side effects of many antipsychotic drugs include theso-called extrapyramidal symptoms, such as rigidity and tremor,continuous restless walking, and tardive dyskinesia which causes facialgrimacing, and involuntary movements of the face and extremities.Orthostatic hypotension is also common. Thus, there also exists a needin the art for antipsychotic drugs that produce fewer or less severemanifestations of these common side effects.

In addition, because of the frequent long term administration ofneuroleptics and the problems with patient compliance, there is afurther need in the art for long lasting neuroleptics, which can beformulated into sustained release depot preparations, without the sideeffects previously mentioned.

Moreover, there has been a need for drugs that can produce otherbiological effects. For example, relief from pain has been an age-oldaspiration which has led to the discovery of natural and syntheticanalgetics. Nevertheless, the need for safe and effective analgetics hascontinued to the present day.

SUMMARY OF THE INVENTION

This invention aids in fulfilling these needs in the art by providing acompound of the formula:

wherein

X is —O—, —S—, —NH—, or —N(R₂)—

R₂ is selected from the group consisting of lower alkyl, aryl loweralkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl andphenylsulfonyl groups;

p is 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine,iodine, lower alkoxy, trifluoromethyl, nitro, or amino;

Q₁ is selected from the group consisting of:

where

Z is

 and

Y₂ is selected from the group consisting of:

in which (R₁) is —CR₂₄R₂₇—(CR₂₃R₂₄)_(n)—CR₂₄R₂₇— where n is 0,1,2, or 3;

—CHR₂₄—CH═CH—CHR₂₄—,

—CHR₂₄C≡C—CHR₂₄—,

—CHR₂₄—CH═CH—CR₂₃R₂₄—CHR₂₄—,

—CHR₂₄—CR₂₃R₂₄—CH═CH—CHR₂₄—,

—CHR₂₄—C≡C—CR₂₃R₂₄—CHR₂₄—, or

—CHR₂₄—CR₂₃R₂₄—C≡C—CHR₂₄—,

the —CH═CH— bond being cis or trans;

R and m are as defined hereinafter;

R₂₃ is hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, arylalkyloxy,alkanoyloxy, hydroxy lower alkyl, alkoxy lower alkyl, aryloxy loweralkyl, arylalkyl oxy lower alkyl, alkanoyloxy lower alkyl or

where

Z₁ is lower alkyl, —OH, lower alkoxy, —CF₃, —NO₂, —NH₂ or halogen; and

R₂₄ is hydrogen, alkyl, aryl, hydroxy lower alkyl, alkoxy lower alkyl,aryloxy lower alkyl, arylalkoxy lower alkyl, alkanoyloxy lower alkyl or

where

Z₁ is as previously defined;

R₂₇ is hydrogen or R₂₄ and R₂₇ taken together with the carbon to whichthey are attached form C═O or C═S;

and R and m are as defined hereinafter;

where R₁ is as previously defined, and R₃ is hydrogen or —OCH₃;

where R₁ is as previously defined; and

R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy,tri(C₁-C₆)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl,amino, mono- or dialkylamino, (C₁-C₁₈)acyl amino, (C₁-C₁₈)alkanoyl,trifluoromethyl, chlorine, fluorine, bromine, nitro, —O—C(═O)-(C₁-C₁₈straight or branched chain) alkyl or —C(═O)aryl; in which aryl is phenylor

where R₅ is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine,fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino,nitro, cyano, trifluoromethyl, trifluoromethoxy;

where R₁ and R₄ are as previously defined;

where either one of X_(y) or X_(z) is —C(═O)— and the other is —CH₂—;and

R₅′ is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, orbromine; and

R₁ is as previously defined;

where R₁ and R₄ are as previously defined;

where A is —C(═O)—, —C(═S)—, —C(═CH₂)—, —C(═O)CH₂—, —CH₂CH₂—, —CR₂₆═N—,or —CR₂₅R₂₆—;

R₂₅ is hydrogen, lower alkyl, hydroxy or alkanoyloxy;

R₂₆ is hydrogen or lower alkyl;

either one of B_(y) and B_(z) is CH or N and the other is CH;

U is O or S;

q is 1, 2, 3 or 4, and R₁ and R₄ are as previously defined;

where R₁ is as previously defined;

wherein R₁, R₄ and q are as defined above; and

R₂₈ is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, phenyl or substitutedphenyl;

wherein R₁, R₄ and q are as defined above;

R₂₉ and R₃₀ are hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, phenyl orsubstituted phenyl;

R₃₁ and R₃₂ are hydrogen, hydroxy, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,phenyl, substituted phenyl, hydroxymethyl, or CHOR₃₃ where R₃₃ is(C₁-C₁₈)alkanoyl; or

either R₂₉ and R₃₀ taken together or R₃₁ and R₃₂ taken together with thecarbon group to which they are attached form a C═O or C═S group;

where R₁, R₄, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂ and q are as defined above;

where R₁, R₄, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂ and q are as defined above;

wherein R₁ and R₄ are previously defined and m is defined hereinafter;

where R₁ is as previously defined;

Q₂ is S, NH, or —CH₂—; and

R and m are as defined hereinafter;

where R₁ is as previously defined;

where R₁, and R₄ are as previously defined and m is as definedhereinafter;

where R₁, R₄ are as previously defined and m is as defined hereinafter;

—R₁—O—R₁₂  (18)

where R₁₂ is selected from the group consisting of:

hydrogen,

alkyl,

—C(═O)-(C₁-C₁₈ straight chain or branched) alkyl,

—C(═O)—NR₁₃R₁₄,

—C(═O)—NR₁₅R₁₆,

—S(═O)₂—R₁₇, and

where R₁₃ is selected from the group consisting of hydrogen and(C₁-C₁₈)alkyl groups;

where R₁₄ is selected from the group consisting of hydrogen and(C₁-C₁₈)alkyl groups;

where NR₁₅R₁₆ taken together form a ring structure selected from thegroup consisting of piperidinyl, morpholinyl and piperazinyl;

where R₁₇ is selected from the group consisting of lower alkyl and arylgroups;

where R₄ is previously defined and m is defined hereinafter;

—R₁—NR₁₈R₁₉  (19)

where R₁₈ and R₁₉ are independently selected from the group consistingof:

hydrogen,

(C₁-C₁₂ straight or branched chain) alkyl,

—C(═O)—O—(C₁-C₁₈) alkyl,

—C(═O)-(C₁-C₁₈) alkyl;

—C(═O)-pyridyl or

where NR₁₈R₁₉ taken together form a ring structure selected from thegroup consisting of piperidinyl, morpholinyl and piperazinyl; where thepiperidinyl or piperazinyl ring is optionally substituted by

where R₁, X, Y, p, R₄ and R₂₈ are as previously defined and m is definedhereinafter;

—R₁—S—R₁₂  (20)

where R₁ and R₁₂ are as previously defined;

where R₁, R₄ and R₂₈ are as previously defined; and

where

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine,fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro,lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl,trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl,dialkylaminocarbonyl, formyl,

—C(═O)-alkyl,

—C(═O)-O-alkyl,

—C(═O)-aryl,

—C(═O)-heteroaryl,

—CH(OR₇)-alkyl,

—C(═W)-alkyl,

—C(═W)-aryl, and

—C(═W)-heteroaryl;

alkyl is (C₁-C₁₈)alkyl;

aryl is as previously defined;

heteroaryl is

Q₃ is —O—, —S—, —NH—, —CH═N—;

W is CH₂ or CHR₈ or N—R₉;

R₇ is hydrogen, alkyl, or alkanoyl;

R₈ is lower alkyl;

R₉ is hyroxy, alkoxy, or —NHR₁₀; and

R₁₀ is hydrogen, alkyl, (C₁-C₃)acyl, aryl, —C(═O)aryl or—C(═O)heteroaryl, where aryl and heteroaryl are as defined above; and

m is 1, 2, or 3;

with the proviso that in formula (14) Z is not

 when X is —S—, Q₂ is —CH₂—, Y is hydrogen, lower alkyl, lower alkoxy,halogen, hydroxy or trifluoromethyl, and p is 1 or 2;

with the proviso that in formula (4) R₄ is not H when R₁ is —(CH₂)₂₋₅—,Z is not

X is —S—, Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy ortrifluoromethyl, and p is 1 or 2;

with the proviso that in formula (14) Z is not

 when X is —NH— or —N(R₂)—, Y is hydrogen, halogen, lower alkyl, loweralkoxy, hydroxy or trifluoromethyl and Q₂ is —CH₂—;

with the proviso that in formula (14) Z is not

 when X is —O—, Q₂ is —CH₂—, Y is hydrogen, lower alkyl, lower alkoxy,hydroxy or halogen, and p is 1 or 2;

with the proviso that in formula (14) Z is not

 when X is —S—, Q₂ is —CH₂—, Y is hydrogen, halogen, lower alkyl, loweralkoxy or hydroxy, p is 1 or 2, R is hydrogen, and m is 1;

with the proviso that in formula (14) Z is not

 when X is —N(R₂)—, Q₂ is —CH₂—, R is chlorine, fluorine, bromine,iodine, lower alkyl, lower alkoxy, lower alkyl thio, lower mono- ordialkylamino, amino, cyano, hydroxy, trifluoromethyl; R₂ is aryl; Y ishydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2;

with the proviso that in formula (14) Z is not

 when X is —NH— or —N(R₂)—, where R₂ is lower alkyl, aryl lower alkyl,or phenylsulfonyl, Y is hydrogen, halogen, lower alkyl, lower alkoxy orhydroxy, p is 1 or 2 and Q₂ is —CH₂—;

with the proviso that Y₂ is not the moiety of formula (8) when Z is

 X is O, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine,fluorine, bromine, iodine or a hydroxyl group;

with the proviso that in formula (1) Z is not

 when X is O or S, Y is hydrogen, R is hydrogen, (C₁-C₄)alkyl, chlorine,fluorine, bromine, iodine, cyano, (C₁-C₄)alkoxy, aryl, —COOR₂₅ where R₂₅is (C₁-C₄)alkyl;

with the proviso that in formula (1) Z is not

 when X is —S—, R₁ is —(CH₂)₂₋₅—, R is H, and m=1;

with the proviso that in formula (7) R₄ is not hydrogen when Y is 6-F, Xis —O—, Z is

 and n is 2, 3 or 4;

with the proviso that in formula (18) R₁₂ is not H when Z is

 X is —NH— or —N(R₂)— where R₂ is lower alkyl, aryl lower alkyl, orphenylsulfonyl, Y is hydrogen, lower alkyl, lower alkoxy, chlorine,fluorine, bromine, iodine or a hydroxyl group and p is 1 or 2;

with the proviso that in formula (18), R₁₂ is not H when X is —N(R₂)—,where R₂ is phenyl, Z is

 and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine,bromine, iodine or a hydroxyl group;

with the proviso that in formula (19), R₁₈ and R₁₉ are not lower alkylwhen Z is

 X is —N(R₂)— and R₂ is aryl and Y is hydrogen, lower alkyl, loweralkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

with the proviso that in formula (19), when X is —O—, Z is

 and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine,bromine, iodine or a hydroxyl group, R₁₈ and R₁₉ are not lower alkyl;

with the proviso that in formula (19), R₁₈ and R₁₉ are not hydrogen whenR₁ is —(CH₂)₂₋₅—, Z is

X is —O—, and Y is 6-F;

all geometric, optical and stereoisomers thereof, or a pharmaceuticallyacceptable acid addition salt thereof.

This invention also provides compounds selected from formula I which aresuitable for acylation with (C₄-C₁₈)carboxylic acids or reactivefunctional derivatives thereof to form highly lipophilic esters, amidesand carbamates, which compounds are also compounds of this invention.Such selected compounds possess a hydroxyl group attached to either analiphatic or aromatic carbon atom capable of forming the highlylipophilic esters of the invention, a primary or secondary nitrogen atomincluding the nitrogen at the 1-position of an indazole ring systemcapable of forming the highly lipophilic amides of the invention. Theprimary or secondary nitrogen atom may alternatively be acylated with a(C₄-C₁₈)alkoxycarbonyl chloride to form a highly lipophilic carbamatederivative of the invention.

The invention also provides for the highly lipophilic compounds whichprovide long acting pharmaceutical effects when administered in the formof depot preparations.

This invention also provides a pharmaceutical composition, whichcomprises a compound of the invention and a pharmaceutically acceptablecarrier therefor. In one embodiment of the invention, the pharmaceuticalcomposition is an antipsychotic composition comprising a compound of theinvention in an amount sufficient to produce an antipsychotic effect.

In addition, this invention provides a method of treating psychoses,which comprises administering to a patient a pharmaceutically effectiveamount of a compound of the invention.

Further, this invention provides a method of sustained release of apharmaceutically effective amount of a lipophilic compound of theinvention in the form of a depot preparation.

Finally, this invention provides a method of alleviating pain byadministering to a patient a pain-relieving amount of a compound of theinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The compounds of this invention are useful as antipsychotic drugs and asanalgesic agents. The compounds of the invention can contain a varietyof different substituents and chemical groups. As used herein, when theterm “lower” is mentioned in connection with the description of aparticular group, the term means that the group it is describingcontains from 1 to 6 carbon atoms.

The term “alkyl” as used herein refers to a straight or branched chainhydrocarbon group having up to 18 carbon atoms and containing nounsaturation, for example, methyl, ethyl, isopropyl, 2-butyl, neopentyl,n-hexyl or pentadecyl.

The term “alkoxy” as used herein refers to a monovalent substituentcomprising an alkyl group linked through an ether oxygen having its freevalence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy,butoxy, or pentoxy.

The term “alkylene” as used herein refers to a bivalent radical of alower branched or unbranched alkyl group having valence bonds on twoterminal carbons thereof, for example, ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), or isopropylene (—CH(CH₃)CH₂—).

The term “cycloalkyl” refers to a saturated hydrocarbon group possessingat least one carbocyclic ring, the ring containing from 3 to 10 carbonatoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclodecyl and the like.

The term “alkanoyl” refers to the radical formed by removal of thehydroxyl function from an alkanoic acid. More particularly, the term“alkanoyl” as used herein refers to an alkyl carbonyl moiety containingfrom 2 to 18 carbon atoms, e.g.

CH₃—C(═O)—,

CH₃—CH₂—C(═O)—,

etc.

Examples of alkanoyl groups are formyl, acetyl, propionyl,2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl, and the like.

The term “alkanoic acid” refers to a compound formed by combination of acarboxyl group with a hydrogen atom or alkyl group. Examples of alkanoicacids are formic acid, acetic acid, propanoic acid, 2,2-dimethylaceticacid, hexanoic acid, octanoic acid, decanoic acid, and the like.

The term “aryl lower alkyl” refers to compounds wherein “aryl” and“loweralkyl” are as defined above.

The term “lower alkylthio” refers to a monovalent substituent having theformula lower alkyl-S—.

The term “phenylsulfonyl” refers to a monovalent substituent having theformula phenyl-SO₂—.

The term “acyl” refers to a substituent having the formula loweralkyl-C(═O)— or CF₃—C(═O)— or aryl-C(═O)— or heteroaryl-C(═O)—.

The term “lower monoalkylamino” refers to a monosubstituted derivativeof ammonia, wherein a hydrogen of ammonia is replaced by a lower alkylgroup.

The term “lower dialkylamino” refers to a disubstituted derivative ofammonia, wherein two hydrogens of ammonia are replaced by lower alkylgroups.

The term “acylamino” refers to a primary or secondary amine, wherein ahydrogen of the amine is replaced by an acyl group, where acyl is aspreviously defined.

The term “dialkylaminocarbonyl” refers to a derivative of an acid,wherein the hydroxyl group of the acid is replaced by a lowerdialkylamino group.

The term “aroyl” refers to a disubstituted carbonyl, wherein at leastone substituent is an aryl group, where “aryl” is as previously defined.

Unless otherwise indicated, the term “halogen” as used herein refers toa member of the halogen family selected from the group consisting offluorine, chlorine, bromine, and iodine.

Throughout the specification and appended claims, a given chemicalformula or name shall encompass all geometric, optical and stereoisomersthereof where such isomers exist.

A. COMPOUNDS OF THE INVENTION

The compounds of this invention can be represented by the followingformula:

wherein

X is —O—, —S—, —NH—, or —N(R₂)—;

R₂ is selected from the group consisting of lower alkyl, aryl loweralkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl andphenylsulfonyl groups;

p is 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine,iodine, lower alkoxy, trifluoromethyl, nitro, or amino;

Q₁ is selected from the group consisting of:

where Z is

and

Y₂ is selected from the group consisting of:

in which (R₁) is —CR₂₄R₂₇—(CR₂₃R₂₄)_(n)—CR₂₄R₂₇— where n is 0,1,2, or 3;or

—CHR₂₄—CH═CH—CHR₂₄—,

—CHR₂₄—C≡C—CHR₂₄—,

—CHR₂₄—CH═CH—CR₂₃R₂₄—CHR₂₄—,

—CHR₂₄—CR₂₃R₂₄—CH═CH—CHR₂₄—,

—CHR₂₄—C≡C—CR₂₃R₂₄—CHR₂₄—, or

—CHR₂₄—CR₂₃R₂₄—C≡C—CHR₂₄—,

the —CH═CH— bond being cis or trans;

R₂₃ is hydrogen, (C₁-C₁₈) linear alkyl, phenyl, hydroxy, (C₁-C₁₈)alkoxy,aryloxy, aryl(C₁-C₁₈)alkyloxy, (C₁-C₁₈)alkanoyloxy, hydroxy(C₁-C₆)alkyl,(C₁-C₁₈)alkoxy(C₁-C₆)alkyl, phenyl(C₁-C₆)alkyloxy,aryl(C₁-C₁₈)alkyloxy(C₁-C₆)alkyl or (C₁-C₁₈)alkanoyloxy(C₁-C₆)alkyl or

where Z₁ is lower alkyl, —OH, lower alkoxy, —CF₂, —NO₂, —NH₂ or halogen;and

R₂₄ is hydrogen, (C₁-C₁₈) linear alkyl, phenyl, hydroxy(C₁-C₆)alkyl,(C₁-C₁₈)alkoxy(C₁-C₆)alkyl, phenyl(C₁-C₆)alkyloxy,aryl(C₁-C₁₈)alkyloxy(C₁-C₆)alkyl or (C₁-C₁₈)alkanoyloxy(C₁-C₆)alkyl or

where Z₁ is as previously defined;

R₂₇ is hydrogen or R₂₄ and R₂₇ taken together with the carbon to whichthey are attached form C═O or C═S; and

R and m are as defined hereinafter;

where R₁ is as previously defined, and R₃ is hydrogen or —OCH₃;

where R₁ is as previously defined; and

R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy,tri(C₁-C₆)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl,amino, mono- or dialkylamino, (C₁-C₁₈)acyl amino, (C₁-C₁₈)alkanoyl,trifluoromethyl, chlorine, fluorine, bromine, —O—C(═O)-(C₁-C₁₈straightor branched chain) alkyl or —C(═O)aryl;

in which aryl is phenyl or

where R₅ is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine,fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino,nitro, cyano, trifluoromethyl, trifluoromethoxy;

where R₁ and R₄ are as previously defined;

where either one of X_(y) or X_(z) is —C(═O)— and the other is —CH₂—;and

R₅′ is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, orbromine; and

R₁ is as previously defined;

where R₁ and R₄ are as previously defined;

where A is —C(═O)—, —C(═S)—, —C(═CH₂)—, —C(═O)CH₂—, —CH₂CH₂—, —CR₂₆═N—or —CR₂₅R₂₆—;

R₂₅ is hydrogen, (C₁-C₆)alkyl, hydroxy or (C₁-C₁₈)alkanoyloxy;

R₂₆ is hydrogen or (C₁-C₆)alkyl;

either one of B_(y) and B_(z) is CH or N and the other is CH;

U is O or S;

q is 1, 2, 3 or 4, and R₁ and R₄ are as previously defined;

where R₁ is as previously defined;

wherein R₁, R₄ and q are as defined above; and

R₂₈ is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, phenyl or substitutedphenyl;

wherein R₁, R₄ and q are as defined above;

R₂₉ and R₃₀ are hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, phenyl orsubstituted phenyl;

R₃₁ and R₃₂ are hydrogen, hydroxy, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl,phenyl, substituted phenyl, hydroxymethyl, or CHOR₃₃ where R₃₃ is(C₁-C₁₈)alkanoyl; or

either R₂₉ and R₃₀ taken together or R₃₁ and R₃₂ taken together with thecarbon group to which they are attached form a C═O or C═S group;

where R₁, R₄, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂ and q are as defined above;

where R₁, R₄, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂ and q are as defined above;

wherein R₁ and R₄ are previously defined and m is defined hereinafter;

where R₁ is as previously defined;

Q₂ is S, NH, or —CH₂—; and

R and m are as defined hereinafter;

where R₁ is as previously defined;

where R₁ and R₄ are as previously defined and m is defined hereinafter;

where R₁ and R₄ are as previously defined and m is defined hereinafter;

—R₁—O—R₁₂  (18)

where R₁₂ is selected from the group consisting of:

hydrogen,

alkyl,

—C(═O)-(C₁-C₁₈ straight chain or branched) alkyl,

—C(═O)—NR₁₃R₁₄,

—C(═O)—NR₁₅R₁₆,

—S(═O)₂—R₁₇, and

where R₁₃ is selected from the group consisting of hydrogen and (C₁-C₁₈)alkyl groups;

where R₁₄ selected from the group consisting of hydrogen and (C₁-C₁₈)alkyl groups;

where NR₁₅R₁₆ taken together form a ring structure selected from thegroup consisting of piperidinyl, morpholinyl and piperazinyl;

where R₁₇ selected from the group consisting of (C₁-C₁₈)alkyl and arylgroups;

where R₄ previously defined and m is defined hereinafter;

—R₁—NR₁₈R₁₉  (19)

where R₁₈ and R₁₉ are independently selected from the group consistingof:

hydrogen,

(C₁-C₁₈ straight or branched chain) alkyl,

—C(═O)—O-(C₁-C₁₈) alkyl,

—C(═O)-(C₁-C₁₈) alkyl;

—C(-O)-pyridyl;

where NR₁₈R₁₉ taken together form a ring structure selected from thegroup consisting of piperidinyl, morpholinyl and piperazinyl;

where the piperidinyl or piperazinyl ring is optionally substituted by

where X, Y, p, R₁, R₄ and R₂₈ are as previously defined and m is definedhereinafter;

—R₁—S—R₁₂  (20)

where R₁ and R₁₂ are as previously defined;

where R₁, R₄ and R₂₈ are as previously defined; and

where

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine,fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro,lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl,trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl,dialkylaminocarbonyl, formyl,

—C(═O)-alkyl,

—C(═O)—O-alkyl,

—C(═O)-aryl,

—C(═O)-heteroaryl,

—CH(OR₇)-alkyl,

—C(═W)-alkyl,

—C(═W)-aryl, and

—C(═W)-heteroaryl;

alkyl is (C₁-C₁₈)alkyl;

aryl is as previously defined;

heteroaryl is

Q₃ is —O—, —S—, —NH—, —CH═N—;

W is CH₂ or CHR₈ or N—R₉;

R₇ is hydrogen, alkyl, or alkanoyl;

R₈ is lower alkyl;

R₉ is hydroxy, or —NHR₁₀; and

R₁₀ is hydrogen, lower alkyl, (C₁-C₁₈)acyl, aryl, —C(═O)-aryl or—C(═O)-heteroaryl, where aryl and heteroaryl are as defined above; and

m is 1, 2, or 3;

with the proviso that in formula (14) Z is not

 when X is—S—, Q₂ is —CH₂—, Y is hydrogen, lower alkyl, lower alkoxy,halogen, hydroxy or trifluoromethyl, and p is 1 or 2;

with the proviso that in formula (4) R₄ is not H when R₁ is —(CH₂)₂₋₅—,Z is not

 X is —S—, Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy ortrifluoromethyl, and p is 1 or 2;

with the proviso that in formula (14) Z is not

 when X is —NH— or —N(R₂)—, Y is hydrogen, halogen, lower alkyl, loweralkoxy, hydroxy or trifluoromethyl and Q₂ is —CH₂—;

with the proviso that in formula (14) Z is not

 when X is —O—, Q₂ is —CH₂—, Y is hydrogen, lower alkyl, lower alkoxy,hydroxy or halogen, and p is 1 or 2;

with the proviso that in formula (14) Z is not

 when X is —S—, Q₂ is —CH₂—, Y is hydrogen, halogen, lower alkyl, loweralkoxy or hydroxy, p is 1 or 2, R is hydrogen, and m is 1;

with the proviso that in formula (14) Z is not

 when X is —N(R₂)—, Q₂ is —CH₂—, R is chlorine, fluorine, bromine,iodine, lower alkyl, lower alkoxy, lower alkyl thio, lower mono- ordialkylamino, amino, cyano, hydroxy, trifluoromethyl; R₂ is aryl; Y ishydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2;

with the proviso that in formula (14) Z is not

 when X is —NH— or —N(R₂)—, where R₂ is lower alkyl, aryl lower alkyl,or phenylsulfonyl, Y is hydrogen, halogen, lower alkyl, lower alkoxy orhydroxy, p is 1 or 2 and Q₂ is —CH₂—;

with the proviso that Y₂ is not the moiety of formula (8) when Z is

X is O, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine,fluorine, bromine, iodine or a hydroxyl group;

with the proviso that in formula (1) Z is not

 when X is O or S, Y is hydrogen, R is hydrogen, (C₁-C₄)alkyl, chlorine,fluorine, bromine, iodine, cyano, (C₁-C₄)alkoxy, aryl, —COOR₂₅ where R₂₅is (C₁-C₄)alkyl;

with the proviso that in formula (1) Z is not

 when X is —S—, R₁ is —(CH₂)₂₋₅, R is H, and m=1;

with the proviso that in formula (7) R₄ is not hydrogen when Y is 6—F; Xis —O—, Z is

 n is and 2, 3 or 4;

with that the proviso that in formula (18) R₁₂ is not H when Z is

 X is —NH— or —N(R₂)— where R₂ is lower alkyl, aryl lower alkyl, orphenylsulfonyl, Y is hydrogen, lower alkyl, lower alkoxy, chlorine,fluorine, bromine, iodine or a hydroxyl group and p is 1 or 2;

with the proviso that in formula (18), R₁₂ is not H when X is —N(R₂)—,where R₂ is phenyl, Z is

 and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine,bromine, iodine or a hydroxyl group;

with the proviso that in formula (19), R₁₈ and R₁₉ are not lower alkylwhen Z is

 X is —N(R₂)— and R₂ is aryl and Y is hydrogen, lower alkyl, loweralkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

with the proviso that in formula (19), when X is —O—, Z is

 and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine,bromine, iodine or a hydroxyl group, R₁₈ and R₁₉ are not lower alkyl;

with the proviso that in formula (19), R₁₈ and R₁₉ are not hydrogen whenR₁ is —(CH₂)₂₋₅—, Z is

 X is —O—, and Y is 6—F;

all geometric, optical and stereoisomers thereof, or a pharmaceuticallyacceptable acid addition salt thereof.

When the compounds of the invention are represented by the followingformula:

where Q₁ is selected from the group consisting of:

the substituent X in formula (I) is selected from the group consistingof —O—, —S—, —NH—, or —N(R₂)—. When the substituent X is —O—, thecompounds of the invention contain a 1,2-benzisoxazole nucleus, and whenX is —S—, the compounds of the invention contain a 1,2-benzisothiazolenucleus. When X is —NH— or —N(R₂)—, the compounds of the inventioncontain the indazole nucleus.

When p in formula (I) is 1, the substituent Y is selected from the groupconsisting of hydrogen, lower alkyl, hydroxyl, halogen, lower alkoxy,—CF₃, —NO₂ and —NH₂. The substituent Y is preferably in the 5- or6-position of the ring. Moreover, in the preferred embodiments of theinvention, the substituent Y is hydrogen, hydroxy, chlorine, bromine, orfluorine, and in the particularly preferred compounds of the invention,Y is fluorine, especially in the 6-position of the ring.

When p in formula (I) is 2 and X is —O—, each Y substituent can beindependently selected from lower alkoxy, hydroxy or halogen groups,preferably methoxy groups.

When the substituent Y₂ has the formula (b)(1):

and R₁ contains unsaturation, R₁ preferably has the formula

—CH₂—CH═CH—CH₂—.

When the substituent Y₂ has the formula (b)(3):

the substituent R₄ is preferably halogen or (C₁-C₆)alkyl carbonyl and nis 3.

When the substituent Y₂ has the formula (b)(4):

the substituent R₄ is preferably hydrogen or —C(═O)CH₃ and n ispreferably 1 or 2.

When the substituent Y₂ has the formula (b)(5):

the substituent R₅′ is preferably —OCH₃ and n is preferably 3.

When the substituent R₄ has the formula (b)(6):

the substituent R₄ is preferably —C(═O)CH₃ and n is preferably 3.

When the substituent Y₂ has the formula (b)(7):

the substituent R₄ is preferably hydrogen or methyl and n is preferably2.

When the substituent Y₂ has the formula (b)(8):

the value of n is preferably 3 or 4.

When the substituent Y₂ has the formula (b)(9):

the substituent R₆ is preferably —CH₂—CH═CH₂—CH₂— when R₆ containsunsaturation.

When the substituent R is

the substituent Q₃ is preferably —CH═N; and the substituent W ispreferably CH₂, the substituent R₈ in CHR₈ is preferably CH₃, thesubstituent R₉ in N—R₉ is preferably hydroxy, lower alkoxy, or NH₂, andthe substituent R₁₀ in NHR₁₀ is preferably hydrogen.

The value of n in the foregoing formulas can be 2, 3, 4, or 5, andpreferably is 2, 3, or 4. In the particularly preferred compounds of theinvention n is 2 or 3.

When X in the compounds of the invention is —N(R₂)—, the substituent R₂is selected from the group consisting of lower alkyl, aryl lower alkyl,aryl, cycloalkyl, aroyl, alkanoyl, alkanoyloxy and phenylsulfonylgroups.

The substituent Z can be

in which case the compounds of the invention are heteroarylpiperidinederivatives, or

in which case the compounds are heteroarylpiperazine derivatives. Whenthe substituent Q₁ has the formula

the compounds of the invention are heteroarylpyrrolidines. The preferredcompounds of the invention are the heteroarylpiperidines, i.e. compoundsin which Z is

The compounds of the invention can contain one, two, or threeR-substituents. The substituent R can be hydrogen, lower alkyl,(C₁-C₁₈)alkoxy, hydroxyl, carboxyl, Cl, F, Br, I, amino, (C₁-C₁₈)mono ordialkyl amino, —NO₂, lower alkyl thio, —OCF₃, cyano, acylamino, —CF₃,trifluoroacetyl (i.e. —C(═O)—CF₃), aminocarbonyl (i.e. —C(═O)—NH₂),dialkylaminocarbonyl,

formyl,

—C(═O)-alkyl,

—C(═O)—O-alkyl,

—C(═O)-aryl,

—C(═O)-heteroaryl, or

—CH(OR₇)-alkyl,

—C(═W)-alkyl,

—C(═W)-aryl, or

—C(═W)-heteroaryl;

alkyl is (C₁-C₁₈) alkyl;

aryl is phenyl or

where R₅ is hydrogen, lower alkyl, (C₁-C₆)alkoxy, hydroxy, Cl, F, Br, I,(C₁-C₁₈)alkylamino, —NO₂, —CN, —CF₃, —OCF₃;

heteroaryl is

Q₃ is —O—, —S—, —NH—, —CH═N—;

W is CH₂ or CHR₈ or N—R₉;

R₇ is hydrogen, alkyl, or alkanoyl;

R₈ is lower alkyl;

R₉ is hydroxy, alkoxy, or —NHR₁₀; and

R₁₀ is hydrogen, lower alkyl, (C₁-C₁₈)acyl, aryl, —C(═O)-aryl or —C(═O)—heteroaryl, where aryl and heteroaryl are as defined above; and

m is 1, 2, or 3.

When the compounds of the invention contain two or three R-substituents,each of the R-substituents can be independently selected from the abovesubstituents. Preferably, each of the R-substituents is selected fromthe group consisting of hydrogen, (C₁-C₁₈)alkyl, (C₁-C₁₈)alkoxy,hydroxyl, —COCF₃, (C₁-C₁₈)alkanoyl, Cl, F, Br, I, (C₁-C₃)alkylamino,—NO₂, —CF₃, —OCF₃,

—C(═O)-lower alkyl, and

—CH(OR₇)-lower alkyl.

The compounds of the present invention are prepared in the followingmanner. The substituents R, R₁, R₂, R₃, etc., X, Y, and Z and theintegers m, n, and p are as defined above unless indicated otherwise.

B. PREPARATION OF COMPOUNDS OF THE INVENTION

The compounds of the invention can generally be prepared by reacting apiperidine or a piperazine of the formula:

or a pyrrolidine of the formula:

under alkylating conditions with a compound of the formula:

HAL-Y₂   (4)

where HAL is Cl, Br, or I. The procedures that can be employed forpreparing the piperidines, the piperazines, and the pyrrolidines and thealkylating agents identified by the above formulas will now be describedin detail.

1. Preparation of 3-(1-unsubstituted-4-piperaziny)-1H-indazoles

Compounds of the formulae:

for use in synthesizing the indazoyl-substituted piperazines of theinvention can be prepared as follows.

A substituted aryl ester of formula (7) is selected,

where R₁₁ is lower alkyl and Hal is a halogen selected from the groupconsisting of Cl, Br, and I. The ester of formula (7) is reacted withhydrazine, H₂NNH₂, under standard hydrazide formation conditions.Typically, the reaction is carried out in a nonreactive solvent, e.g.ethanol, methanol, or toluene, at a temperature of ambient temperatureto the reflux temperature of the solvent for 4 to 16 hours to form ahydrazide of formula (8):

The hydrazide of formula (8) is reacted with a phenyl sulfonyl halide ofthe formula

where Hal is a halogen selected from the group consisting of Cl and Br,to form a compound of the formula

Typically this reaction is carried out in a basic solvent, such aspyridine or collidine, at a temperature of 0° to 30° C. for 2 to 16hours.

The compound of formula (10) in turns is reacted neat with thionylchloride at a temperature of 50° to 79° C. (reflux temperature for 2 to16 hours to form a compound of formula (11)

Compound (11) is reacted with a compound of formula (12),

where R₁₁ is lower alkyl, under conventional nucleophilic reactionconditions, for example in an inert solvent, such as tetrahydrofuran(THF), toluene, or diethylether, at a temperature of 5° to 50° C. for 1to 16 hours to form a compound having the formula

The compound of formula (13) is then reacted with a condensation agent,such as copper, copper-bronze, or cuprous oxide, in a solvent such asdimethylformamide, dimethylacetamide, or tetramethylurea, at atemperature of 120° to 177° C. for 1 to 16 hours to form apiperazine-substituted phenylsulfonyl indazole of the formula

A cyano-substituted piperazine phenylsulfonyl indazole is then formed byreacting the compound of formula (14) with a conventional cyanationsource, such as a halo-cyanide, e.g. BrCN or ClCN, under conventionalcyanation conditions, typically in an inert solvent, e.g.dimethylsulfoxide (DMSO) or CHCl₃, at ambient temperature for 2 to 16hours to form a compound of formula

The compound of formula (15) is then subjected to reduction by means ofa metal hydride, e.g. lithium aluminum hydride (LiAlH₄). Typically thereduction is carried out under standard reduction conditions in asolvent, such as tetrahydrofuran or diethyl ether, at a temperature of35° to 67° C. for 6 to 16 hours to form a compound of formula (16):

A compound of formula (16) can be formed in an alternative manner byfirst reacting a compound of formula (14) with a strong base, such as ametal alcoholate, e.g. sodium methoxide, sodium ethoxide, or sodiumbutoxide, or with KOH in tetrahydrofuran to form a compound of formula(17):

This reaction is typically carried out in a polar solvent, such as forexample CH₃OH or C₂H₅OH, at a temperature of ambient to 50° C. for 1 to16 hours.

Alternatively, the compound of formula (17) can be formed by reducingcompound (14) with LiAlH₄ under conditions as previously described.

The compound of formula (17) in turn can be reacted with a cyanationreagent, as previously described, to form a cyano substituted piperazineindazole of the formula

which in turn can be reduced with a metal hydride, as previouslydescribed, to form a compound of formula (16).

In an alternative embodiment, a compound of formula (18) can be reactedwith an aqueous mineral acid, e.g. H₂SO₄ or HCl, at a temperature of 50°to 120° C. for 2 to 16 hours to form a compound of formula (16).

2. Preparation of 3-(1-unsubstituted-4-piperazinyl)-1,2-benzisoxazoles

A compound of the formula:

can be prepared according to conventional techniques. Suitableprocedures are described in J. Med. Chem. 1986, 29:359. Compounds offormula (19) are useful for synthesizing the benzisoxazole substitutedpiperazines of the invention.

3. Preparation of 3-(1-unsubstituted-4-piperazinyl)-1,2-benzisothiazoles

A compound of the formula:

for use in synthesizing the benzisothiazole substituted piperazines ofthe invention can be prepared according to the techniques described inJ. Med. Chem. 1986, 29:359, United Kingdom Patent (GB) 2 163 432 A andTetrahedron Letters, Vol 34, No. 41, pp.6525-6528, 1993.

4. Preparation of 3-(1-unsubstituted-4-piperidinyl)-1H-indazoles

A compound of the formula:

for use in synthesizing the indazole-substituted piperidines of theinvention can be prepared using known techniques. For example, suitabletechniques are described in substantial detail in U.S. Pat. No.4,710,573.

5. Preparation of 3-(1-unsubstituted-4-piperidinyl)-1,2-benzisoxazoles

A compound of the formula:

can be prepared by following the teachings from several sources. Forexample, U.S. Pat. No. 4,355,037 contains a detailed description ofcompounds of formula (23) and of methods for preparing the compounds.Additional disclosure of methods for preparing the compounds of formula(23) can be found in U.S. Pat. No. 4,327,103 and in Strupczewski et al.,J. Med. Chem., 28:761-769 (1985). The compounds of formula (23) can beemployed in the synthesis of the benzisoxazole substituted piperidinesof the invention.

6. Preparation of 3-(1-unsubstituted-4-piperidinyl)-1,2-benzisothiazoles

Certain 3-(4-piperidinyl)-1,2-benzisothiazoles can be employed in thesynthesis of the N-(aryloxyalkyl)heteroaryl piperidines of theinvention. Specifically, a benzisothiazole of the formula:

can be reacted with the alkylating agent previously described to formthe N-(aryloxyalkyl)heteroarylpiperidines of the invention. Compounds offormula (24) and their methods of preparation are described in detail inU.S. Pat. No. 4,458,076.

7. Preparation of alkylating agents

The compounds described in Sections 1-6 above can be reacted withalkylating agent as is known in the art. For example, when Y₂ is asdescribed in formula (1), an alkylating agent of the formula:

is reacted to form the N-(aryloxyalkyl)heteroarylpiperidines,piperazines, and pyrrolidines of the invention. The alkylating agents offormula (4) and methods for preparing the alkylating agents aredescribed in U.S. Pat. No. 4,366,162. Additional disclosure can be foundin South African publication EA 86 14522. In addition, procedures formaking alkylating agents are described in the following Examples. Theseprocedures can be employed to make other alkylating agents for use inthis invention.

8. Alkylation of heteroarylpiperidines, piperazines, and pyrrolidines

The heteroarylpiperidines, piperazines, and pyrrolidines described inSections 1-6 above can be reacted under alkylating conditions with thealkylating agents described in Section 7 to form selected compounds ofthis invention. The reaction can be carried out by dissolving thereagents in an inert solvent, such as dimethylformamide, acetronitrile,or butanol, and allowing the reagents to react from a temperature of 50°C. to refluxing of the solvent in the presence of an acid receptor, suchas a base. Examples of suitable bases are alkali metal carbonates, suchas potassium carbonate, sodium carbonate, or sodium bicarbonate. Thereaction can be carried out with or without a catalytic amount of analkaline iodide, such as potassium iodide or sodium iodide, for a timesufficient to form a compound of formula (I) of the invention.Generally, the alkalation reaction is carried out for about 4 to about16 hours, depending on reactivity of the reagents. The reactiontemperature can vary from about 50° to about 120° C. The products can beisolated by treating the reaction product with water, extracting theproduct into an organic solvent that is immiscible in water, washing,drying, and concentrating the organic solvent to yield the free base,and then, if indicated, converting the resulting compound to an acidaddition salt in a conventional manner.

In addition, the compounds of formula 19 where R₁₈R₁₉ are both hydrogenmay be prepared from the phthalimido compound of formula 7 by treatmentwith base such us, for example, hydrazine as is known in the art.

More specifically, certain of the compounds of the invention can besynthesized by the following methods:

A. Synthesis of Phthalimides

The phthalimido compounds of the invention of formula (25) can besynthesized

in several ways.

1. Alkylation with an N-haloalkylphthalimide

The heterolarylpiperidines, piperazines and pyrrolidines described inSections 1-6 above are alkylated under known conditions using theappropriate haloalkylphthalimide, preferably an N-bromoalkylphthalimide(26), in a nonprotic

organic solvent such as acetronitrile in the presence of a base such aspotassium carbonate at a temperature of from about room temperature toabout 120° C., preferably from about 80° C. to about 100° C.

2. Reaction with a phthalic anhydride

The heteroarylpiperidines, piperazines and pyrrolidines described inSections 1-6 above are first reacted with a haloalkylnitrile to form thecorresponding substituted nitrile (27) wherein R is a substituent asdefined for R₁ above. The reaction is carried out in a polar, nonproticorganic solvent such as

acetronitrile in the presence of a base such as potassium carbonate at atemperature of from about room temperature to about 120° C., preferablyfrom about 80° C. to about 100° C.

The nitrile is then reduced, for example with lithium aluminum hydridein an organic solvent such as tetrahydrofuran at a temperature of fromabout 0° C. to about 80° C. preferably at about room temperature toyield the corresponding primary amine (28).

The amine(28) is reacted with phthalic anhydride or a substitutedphthalic anhydride or the corresponding phthalic acid under knownconditions, for example in dichloromethane or dimethylformamide attemperatures of from about 10° C. to about 150° C. to yield thecorresponding phthalimido compound. Preferred conditions for thereaction include dichloromethane at room temperature ordimethylformamide a t 135° C.

B. Synthesis of isoindolines

The isoindolines of Formula (29) can be prepared by the followingroutes.

1. Condensation with an α,α′-dibromo-ortho-xylene

The amine (28) is reacted with an α,α′-dibromo-ortho-xylene to obtainthe isoindoline. The reaction is carried out in an organic solvent suchas acetronitrile in the presence of a base such as potassium carbonateat temperatures of from about room temperature to about 150° C.,preferably from about 75° C. to about 100° C.

2. Reduction of a phthalimide

Alternatively, a phthalimido compound of the invention is reduced, forexample with lithium aluminum hydride in an organic solvent such astetrahydrofuran at a temperature of from about 0° C. to about 100° C.,preferably from about 70° C. to about 90° C.

C. Synthesis of tetrahydroquinolines and tetrahydroisoquinolines

The tetrahydroquinolines and tetrahydroisoquinolines of the inventioncan be prepared by alkylating the heteroarylpiperidine, piperazine andpyrrolidines (3,3A) with the appropriate2-bromoacetyltetrahydroquinoline or 2-bromoacetyltetrahydroisoquinolinein the presence of a polar organic solvent such as acetronitrile in thepresence of a base such as potassium carbonate at temperatures of fromabout room temperature to about 150° C., preferably from about 75° C. toabout 100° C. to form the corresponding amide (30,30a).

The amide (30,30a) is reduced, for example with lithium aluminum hydridein an organic solvent such as tetrahydrofuran at a temperature of fromabout 0° C. to about 80° C. preferably at about room temperature toyield the alkyl compound.

9. Preparation of the “depot” compounds of the invention

Selected compounds of the invention possess a hydroxyl group attached toeither an aliphatic or aromatic carbon capable of forming the highlylipophilic esters of this invention or possess a primary or secondarynitrogen atom including the nitrogen at the 1-position of an indazolering system capable of forming the highly lipophilic amides of thisinvention. The primary or secondary nitrogen atom may alternatively beacylated with a C₄-C₁₈ alkoxycarbonyl chloride to form a highlylipophilic carbonate derivative. Representatives of such alcohols andamines and their highly lipophilic derivatives are found in the Examplesof this invention.

It is known in the art that long acting derivatives of drugs may beobtained by such transformation. European Patent Publication No. 260,070discloses the prolonged action of haloperidol decanoate ester.International Publication No. WO 92/06089 discloses sustained releaseamide derivatives of sertindole.

Following are typical examples of compounds of the invention that can beprepared by following the techniques described above:

1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[2-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanonefumarate;

1-[4-[4-[4-(1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanonefumarate;

1-[4-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone;

1-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α-methylbenzenemethanol;

1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(1H-indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanonefumarate;

1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

6-fluoro-3-[1-[3-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazolefumarate;

[4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]phenylmethanone;

1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone;

1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanonefumarate;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methylphenyl]ethanone;

1-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-5-methylphenyl]ethanone;

N-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]acetamidehemifumarate;

6-chloro-3-(1-piperazinyl)-1H-indazole;

1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methylphenyl]ethanonehemifumarate;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;

1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone;

4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzonitrile;

1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(1-benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanonesesquifumarate;

1-[4-[4-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanonehemifumarate;

1-[3,5-dibromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;

1-[4-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]ethanone;

6-fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole;

1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methylmercaptophenyl]ethanone;

1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]phenylmethanone;

1-[3-bromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;

3-[1-[3-[4-(1-ethoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride;

3-[1-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolefumarate;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy-3-methoxyphenyl]pentanone;

2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperdinyl]propoxy]-N-methylbenzenaminehemifumarate;

3-[1-[3-(4-bromo-2-methoxphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]propanone;

4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylamino)phenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-ethoxyphenyl]ethanone;

N-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-dimethylaminophenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methoxyphenyl]ethanonehydrochloride;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2,2,2-trifluoroethanone;

4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanol;

2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]anilinedihydrochloride;

N-[5-acetyl-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide;

3-[1-[3-(4-ethyl-3-methoxyphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride;

1-[3,5-dimethoxy-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;

N-[3-[3-[4-(6-fluoro-1,2-benxoisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamidehemifumarate;

3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]aniline;

3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyaniline;

1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy-3-methylaminophenyl]ethanonefumarate;

N-[3-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]acetamide;

1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanonehydrochloride;

N,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanoneoxime;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]ethanoneoxime O-methyl ether;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanonehydrazone;

6-fluoro-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehydrochloride;

(Z)-1-[4-[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone;

(Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxyphenyl]ethanone;

(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-hydroxyphenyl]ethanonehydrochloride;

(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanone;

6-(3-chloropropoxy)-5-methoxyindole;

6-fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole;

6-fluoro-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehemifumarate;

6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole;

6-fluoro-3-[1-(2-pyrimidinoxy)propyl]-4-piperidinyl]-1,2-benzisoxazolefumarate;

6-aceto-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan;

2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan;

2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-1,4-benzodioxan;

6-(3ochloropropoxy)-7-methoxy-1-tetralone;

6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-tetralone;

N-(3-chloropropyl)-2-benzoxazolinone;

N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone;

N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone;

N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimide;

1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride;

cis-2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)propyl)hexahydro-1H-isoindole-1,3-dionehydrochloride;

N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butyl]phthalimide;

1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride;

cis-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)butyl)hexahydro-1H-isoindole-1,3-dionehydrochloride;

1-[3-[[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]ethanone;

4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2′-methoxyphenyl)butylpiperidinemaleate;

4-(4-bromobutyl)-1-(1,3-dithian-2-yl)ethylbenzene;

1-[4-(1,3-dithian-2-yl)ethyl]phenyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)butylpiperidine;

1-[4-(4′-acetophenyl)butyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-methoxyphenyl]ethanone;

(2,4-difluorophenyl)-[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxalate;

6-fluoro-3-[1-phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazole fumarate;

(E)-1-[4-[(4-bromo-2-butenyl)oxy]-3-methoxyphenyl]ethanone;

4-(3-chloropropoxy)-3-methoxybenzaldehyde;

6-fluoro-3-(3-pyrrolidinyl)-1,2-benzisoxazole hydrochloride;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-hydroxyphenyl]ethanone;

1-[3-acetylamino-4-(3-chloropropoxy)phenyl]ethanone;

N-[2-(3-hydroxypropoxy)phenyl]acetamide;

4-(3-chloropropoxy)-3-methoxybenzaldehyde;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;

(S)-(+)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;

(R)-(−)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2,2-dimethylpropoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-phenylpropoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-(3-chlorophenyl)propoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-(phenylmethyl)propoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-methylpropoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methylpropoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methylbutoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-phenylbutoxy]-3-methoxyphenyl]ethanone;

(+)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-(2-phenylethyl)butoxy]-3-methoxyphenyl]ethanone;

(±)-[4-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1methylethoxy]-3-methoxyphenyl]ethanone;

(E)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-methyl-2-butenyl]oxy]-3-methoxyphenyl]ethanone;

(Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methyl-2-butenyl]oxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-propyl-2-butynyl]oxy]-3-methoxyphenyl]ethanone;

(S)-(+)-1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;

(R)-(−)-1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-3-methylbutoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-phenylpropoxy]-3-methoxyphenyl]ethanone;and

(±)-6-fluoro-3-[1-[3-(2-methyl-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazole.

The compounds of the present invention are useful for treating psychosesby virtue of their ability to elicit an antipsychotic response inmammals. Antipsychotic activity is determined in the climbing mice assayby a method similar to those described by P. Protais, et al.,Psychopharmacol., 50:1 (1976) and B. Costall, Eur. J. Pharmacol., 50:39(1978).

Subject CK-1 male mice (23-27 grams) are group-housed under standardlaboratory conditions. The mice are individually placed in wire meshstick cages (4″×10″) and are allowed one hour for adaption andexploration of the new environment. Then apomorphine is injectedsubcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for30 minutes. Compounds to be tested for antipsychotic activity areinjected intraperioneally or given oral doses at various time intervals,e.g. 30 minutes, 60 minutes, etc. prior to the apomorphine challenge ata screening dose of 10-60 mg/kg.

For evaluation of climbing, 3 readings are taken at 10, 20, and 30minutes after apomorphine administration according to the followingscale:

Climbing Behavior Mice with: Score 4 paws on bottom (no climbing) 0 2paws on the wall (rearing) 1 4 paws on the wall (full climb) 2

Mice consistently climbing before the injection of apomorphine arediscarded.

With full-developed apomorphine climbing, the animals are hanging on tothe cage walls, rather motionless, over long periods of time. Bycontrast, climbs due to mere motor stimulation usually only last a fewseconds.

The climbing scores are individually totaled (maximal score: 6 per mouseover 3 readings) and the total score of the control group (vehicleintraperitoneally-apomorphine subcutaneously) is set to 100%. ED₅₀values with 95% confidence limits, calculated by a linear regressionanalysis, of some of the compounds of the present invention as well as astandard antipsychotic agent are presented in Table 1.

TABLE 1 CLIMBING MOUSE ASSAY COMPOUND (ED₅₀ mg/kg, ip)1-[4-[3-[4-(1H-imdazol-3-yl)-1- 0.98 piperazinyl]propoxy]-3-methoxy-phenyl]ethanone 1-[4-[3-[4-(1,2-benzisoxazol-3-yl)- 0.671-piperidinyl]propoxy]-3-methoxy phenyl]ethanone1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol- 0.0953-yl)-1-piperidinyl]propoxy]-3-methoxy- phenyl]ethanone1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1- 1.6piperidinyl]butoxy]-3-methoxyphenyl] ethanone1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.68piperidinyl]butoxy]-3-methoxyphenyl]ethanone1-[4-[3-[4-(6-fluoro-1,2-benzoisothiazol- 0.163-yl)-1-piperidinyl]propoxy]-3-methoxy- phenyl]ethanone hydrochloride2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.29piperidinyl]ethyl]-1,4-benzodioxan(Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol- 0.613-yl)-1-piperizinyl-2-butenyl]oxy]-3- methoxyphenyl]ethanone1-[4-[4′-acetophenyl]butyl]-4-(6-fluoro- 0.341,2-benzisoxazol-3-yl)piperidine 6-fluoro-3-[1-(3-hydroxypropyl)-4- 4.1piperidinyl]-1,2-benzisoxazole 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-3.31 1-piperidinyl]butyl decanoate fumarate1-[3-aminopropyl]-4-(6-fluoro-1,2-benziisoxazol- 22.63-yl)-piperidine-dihydrochlorideN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 5.01-piperidinyl]ethyl]phthalamideN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 0.481-piperidinyl]ethyl]phthalamide hydrochloride6-fluoro-3-[1-[3-(isoquinol-5-yl)oxy] 0.172propyl]-4-piperidinyl]-1,2-benzisoxazole sesquifumarateN-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)- 0.381-piperidinyl]ethyl]phthalimide hydrochlorideN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 2.91-piperidinyl]ethyl]-3,6-difluorophthalimideN-[2-[4-(6-fluoro-1H-indazol-3-yl)- 1.2 1-piperazinyl]ethyl]phthalimideN-[2-[4-(6-fluoro-1H-imdazol-3-yl)- 0.8 1-piperazinyl]ethyl]phthalimidehydrochloride 2,3-dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol- 0.643-yl]-1-piperidinyl]ethyl]-3-methylene-1H- isoindol-1-one hydrochloride2,3-dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol- 1.173-yl)-1-piperidinyl]ethyl]-3-methyl-1H-isoindol- 1-one hydrochlorideN-[2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.097piperidinyl]ethyl]-4-aminophthalimide fumarateN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 1.6piperidinyl]ethyl]-4-hydroxyphthalimide hydrochloride2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1- 2.2piperazinyl]ethyl]-2,3-dihydro-3-hydroxy-1H- isoindol-1-one hemifumarate2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 1.9piperizinyl]ethyl]-2,3-dihydro-1H-isoindol- 1-oneN-[2-[4-(6-fluoro-1H-indazol-3-yl)-1- 0.37piperizinyl]ethyl]-4-methylphthalimide dihydrochlorideN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.16piperidinyl]ethyl]-3-methoxyphthalimide4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-[2-(2,3- 0.36dihydro-1H-Isoindol-2-yl)ethyl]piperidine dihydrochloride3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.61piperidinyl]ethyl]]-2-methyl-3H-quinazolin-4- one4-(6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro- 0.251H-(isoindol-2-yl)-ethyl]piperizine dimaleateN-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.7piperidinyl]-butyl]phthalimide hydrochloride1-(1,2,3,4-tetrahydro-1H-Isoquinolin-2-yl)-2- 6.25[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]-ethanonehydrochloride ethanolate4-(6-fluoro-1H-indazol-3-yl)-1-[2-(5-fluoro-2,3- 0.16dihydro-1H-Isoindol-2-yl)ethyl]piperazine dimaleate4-(6-fluoro-1H-Indazol-3-yl)-1-[3-(2,3-dihydro- 0.461H-Isoindol-2-yl)propyl]piperazine dimaleateN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.23piperizinyl]ethyl-1,2,3,4-tetrahydroisoquinoline difumarate2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 2.33piperidinyl]-1-(2,3-dihydro-1H-isoindol-2-yl) ethanone fumarate4-(6-fluoro-1H-indazol-3-yl)-1-[2-(5-fluoro-2,3- 0.27dihydro-1H-Isoindol-2-yl)ethyl]piperidine dimaleateN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 1.19piperidinyl]ethyl]-1,2,3,4-tetrahydroquinoline fumarate4-(6-fluoro-1H-imdazol-3-yl)-1-[2-[2,3-dihydro- 0.175-methyl-1H-Isonidol-2-yl)ethyl]piperizine difumarate4-(6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro- 0.354-methyl-1H-isoindol-2-yl)ethyl]piperazine difumarate4-(1H-indazol-3-yl)-1-[2-(2,3-dihydro-5-fluoro- 1.321H-isoindol-2-yl)ethyl]piperazine dimaleateN-[2-[4-(6-fluoro-1H-indazol-3-yl)-1- 0.44 piperidinyl]ethyl]-1,2,3,4-tetrahydroisoquinoline dimaleate Clarapine (standard) 8.1

Antipsychotic response is achieved when the compounds of the presentinvention are administered to a subject requiring such treatment as aneffective oral, parenteral, or intravenous dose of from 0.01 to 50 mg/kgof body weight per day. It is to be understood, however, that for anyparticular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and they do not, to any extent, limit thescope or practice of the invention.

Some of the compounds of the present invention are also useful asanalgetics due to their ability to alleviate pain in mammals. Theanalgetic utility is demonstrated in the phenyl p-quinone writhing assayin mice, a standard assay for analgesia: Proc. Soc. Exptl. Biol. Med.,95:729 (1957). Thus, for instance, the subcutaneous dose effecting anapproximately 50% inhibition of writing (ED₅₀) in mice produced in thisassay is as shown in Table 2.

TABLE 2 INHIBITION OF PHENYLQUINONE INDUCED WRITHING COMPOUND ED₅₀mg/kg, sc 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]- 0.06propoxy]-3-methoxy-phenyl]ethanone 1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-0.17 piperidinyl]propoxy]- 3-methoxyphenyl]ethanone1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 0.031-piperidinyl]propoxy]-3-methoxyphenyl]- ethanone Propoxyphene(standard) 3.9 Pentazocine (standard) 1.3

Analgesia is achieved when the compounds of the present invention areadministered to a subject requiring such treatment as an effective oral,parenteral, or intravenous dose of from 0.01 to 100 mg/kg of body weightper day. It is to be understood, however, that for any particularsubject, specific dosage regimens should be adjusted according to theindividual need and the professional judgment of the personadministering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

Effective amounts of the compounds of the present invention can beadministered to a subject by any one of several methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions.

The compounds of the present invention, while effective themselves, canbe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility, and the like. Preferredpharmaceutically acceptable addition salts include salts of mineralacids, for example, hydrochloric acid, sulfuric acid, nitric acid, andthe like; salts of monobasic carboxylic acids, for example, acetic acid,propionic acid, and the like; salts of dibasic carboxylic acids, forexample, maleic acid, fumaric acid, and the like; and salts of tribasiccarboxylic acids, such as carboxysuccinic acid, citric acid, and thelike.

Effective quantities of the compounds of the invention can beadministered orally, for example, with an inert diluent or with anedible carrier. They can be enclosed in gelatin capsules or compressedinto tablets. For the purposes of oral therapeutic administration,compounds of the invention can be incorporated with an excipient andused in the form of tablets, troches, capsules, elixirs, suspensions,syrups, wafers, chewing guns, and the like. These preparations shouldcontain at least 0.5% of active compound of the invention, but can bevaried depending upon the particular form and can conveniently bebetween 4% to about 70% of the weight of the unit. The amount of activecompound in such a composition is such that a suitable dosage will beobtained. Preferred compositions and preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween 1.0-300 milligrams of the active compound of the invention.

Tablets, pills, capsules, troches, and the like can also contain thefollowing ingredients: a binder, such as microcrystalline cellulose, gumtragacanth, or gelatin; an excipient, such as starch or lactose; adisintegrating agent such as alginic acid, Primogel, corn starch, andthe like; a lubricant such as magnesium stearate or Sterotes; a glidantsuch as colloidal silicon dioxide; and a sweetening agent such assucrose; or saccharin, or a flavoring agent, such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it can contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms can contain variousmaterials that modify the physical form of the dosage unit, for example,as coatings. Thus, tablets or pills can be coated with sugar, shellac,or other enteric coating agents. A syrup can contain, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes, colorings, and flavors. Materials used in preparingthese various compositions should be pharmaceutically pure and non-toxicin the amounts used.

For the purpose of parenteral therapeutic administration, the activecompound of the invention can be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but can be varied between 0.5 and about 50% of the weightthereof. The amount of active compounds in such compositions is suchthat a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

Solutions or suspensions can also include the following components: asterile diluent, such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol, or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates, or phosphates, and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes, or multiple dose vialsmade of glass or plastic.

The highly lipophilic esters, amides and carbamates of the presentinvention are capable of sustained release in mammals for a period ofseveral days or from about one to four weeks when formulated andadministered as depot preparations, as for example, when injected in aproperly selected pharmaceutically acceptable oil. The preferred oilsare of vegetable origin such as sesame oil, cottonseed oil, corn oil,coconut oil, soybean oil, olive oil and the like, or they are syntheticesters of fatty acids and polyfunctional alcohols such as glycerol orpropyleneglycol.

The depot compositions of the present invention are prepared bydissolving a highly lipophilic ester, amide or carbamate of the instantinvention in a pharmaceutically acceptable oil under sterile conditions.The oil is selected so as to obtain a release of the active ingredientover a desired period of time. The appropriate oil may easily bedetermined by consulting the prior art, or without undue experimentationby one skilled in the art.

An appropriate dose of a compound in accordance with this embodiment ofthe invention is from about 0.01 to 10 mg/kg of body weight perinjection. Preferably, the depot formulations of this invention areadministered as unit dose preparations comprising about 0.5 to 5.0 ml ofa 0.1 to 20% weight/weight solution of compound in the oil. It is to beunderstood that the doses set forth herein are exemplary only and thatthey do not, to any extent, limit the scope or practice of theinvention.

The following examples are for illustrative purposes only and are not tobe construed as limiting the invention. All temperatures are given indegrees Centigrade (°C.) unless indicated otherwise.

EXAMPLE 11-[4-[3-[4-(1H-Indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone(A) 2-Bromobenzoic acid 2-phenylsulfonylhydrazide

To a solution of 2-bromobenzoic acid hydrazide (132 g) in pyridine (1.2L) cooled to about 10 C. with an ice bath, was added benzensulfonylchloride (78.3 ml). After complete addition, the reaction was stirred atambient temperature for four hours, and then poured intoice-hydrochloric acid to precipitate a yellow solid, 135 g. The materialwas recrystallized from isopropanol to yield 125 g of 2-bromobenzoicacid 2-phenylsulfonylhydrazide, m.p.=154°-156° C.

(B) α-Chloro-2-bromobenzaldehyde phenylsulfonylhydrazone

A mixture of 2-bromobenzoic acid phenylsulfonylhydrazide (125 g, 350mmol) and thionyl chloride (265 ml) was stirred and refluxed for 2hours. After about 15 minutes of reflux, the solid went into solution.The reaction was permitted to cool, and then it was poured into hexane.The resultant white solid was collected to afford 124 g ofα-chloro-2-bromobenzaldehyde phenylsulfonylhydrazone, m.p.=120°-122° C.

(C)1-[[(Phenylsulfonyl)hydrazono]-(2-bromophenyl)methyl]-4-methylpiperazine

To a stirred solution, under nitrogen, of α-chloro-2-bromobenzaldehydephenylsulfonylhydrazone (271.1 g; 720 mmol) in tetrahydrofuran (THF; 2L), was added dropwise N-methylpiperazine (159.7 g; 1600 mmol). Thereaction was stirred at ambient temperature for three hours, and thenpermitted to stand at ambient temperature for 16 hours. The reaction waschilled in an ice bath, and then filtered to remove the piperazinehydrochloride that was formed. The filtrate was concentrated to yield abrown gum. The gum was triturated with hot acetonitrile, the mixture wascooled in an ice bath, and when cold, was filtered to remove unwantedside product. The filtrate was then concentrated to afford 392.9 g of abrown gum of crude1-[[(phenylsulfonyl)hydrazono]-(2-bromophenyl)methyl]-4-methylpiperazine.

(D) 3-(4-Methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole

A mixture of 1-[[(phenylsulfonyl)hydrazono]-(2-bromophenyl)methyl]-4-methylpiperazine (31.0 g, 80 mmol), copper bronze (3.1g), K₂CO₃ (11.5 g), and dimethylformamide (500 ml), was stirred andrefluxed for 1.5 hours. The reaction was poured into water and theaqueous suspension was stirred vigorously with ethyl acetate. Thebiphasic mixture was filtered through Celite, and subsequently thelayers were separated. The aqueous portion was extracted with anotherportion of ethyl acetate, and the combined extracts were washed (H₂O)and dried (MgSO₄). Concentration of the extract afforded a solid, whichupon trituration with ether gave 19.7 of solid. The solid wasrecrystallized from isopropanol to afford 17.7 g (60%) of product,m.p.=158°-161° C. An analytical sample was obtained by anotherrecrystallization from isopropanol (with charcoal treatment) to affordcolorless crystals of the indazole,3-(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole, m.p.=160°-161°C.

ANALYSIS: Calculated for C₁₈H₂₀N₄O₂S: 60.66% C; 5.66% H; 15.72%, Found:60.45% C; 5.62% H; 15.61% N

(E) 4-[1-(Phenylsulfonyl)-1H-indazol-3-yl]-1-piperazinecarbonitrile

To a stirred mixture of3-(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole (237 g, 0.67mole), K₂CO₃ (102 g, 0.74 mole) and dimethylsulfoxide (DMSO, 2000 ml),under nitrogen, was added cyanogen bromide (72 g, 0.68 mmol) dissolvedin DMSO (525 ml). The reaction was stirred at ambient temperature for5.5 hours and was then poured into H₂O (7 l). The solid, whichprecipitated from solution, was collected by filtration and was washedwell with H₂O affording 168 g (68%) of product. A 5.2 g sample wasrecrystallized twice from ethanol-H₂O yielding 4.0 g of4-[1-(phenylsulfonyl)-1H-indazol-3-yl]-1-piperazinecarbonitrile,m.p.=178°-180° C.

ANALYSIS: Calculated for C₁₈H₁₇N₅O₂S: 58.85% C; 4.66% H; 19.06% N;Found: 59.01% C; 4.63% H; 19.09% N

(F) 3-(1-Piperazinyl)-1H-indazole

To a stirred mixture of4-[1-(phenylsulfonyl)-1H-indazol-3-yl]-1-piperazinecarbonitrile (163 g,0.44 mol) in tetrahydrofuran (2.0 l) was added, dropwise, lithiumaluminum hydride (880 ml; 0.88 mol of a 1M lithium aluminum hydridesolution in tetrahydrofuran). After complete addition, the reaction washeated to reflux and stirred for 6 hours, stirred at ambient temperaturefor one hour and allowed to sit at room temperature overnight. Thereaction was quenched by the careful dropwise addition of water. Afterno more hydrogen could be observed to evolve, the reaction was filteredand the lithium salt filter cake was washed well with tetrahydrofuran.The filtrate was combined with the filtrate of another run (all togetherthe starting material totaled 300 g, i.e. 820 mmol) and the combinedfiltrates were concentrated to afford 372 g of a yellow solid suspendedin water. An attempt was made to partition the product between water anddichloromethane, but the product proved to be only slightly soluble indichloromethane. Therefore, the biphasic product suspension was filteredthrough a course sintered funnel and the white product which wascollected was dried to afford 121 g. The two phases of the filtrate wereseparated and the water was extracted again with dichloromethane. All ofthe dichloromethane phases were combined, washed twice with water, driedwith magnesium sulfate, and concentrated to afford 41 g of a brownresidue. The residue was triturated with diethyl ether and filtered toafford 10 g of a beige solid, m.p.=139°-150° C. The NMR and MS spectrawere consistent with the structure. Recrystallization of 10 g fromtoluene afforded 7.5 g of 3-(1-piperazinyl)-1H-indazole, m.p. 153°-155°C.

(G) 3-(4-Methyl-1-piperazinyl)-1H-indazole

A stirred mixture of3-(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole (13.5 g, 38mmol), methanol (150 ml) and 25% CH₃ONa in methanol (15.3 ml) wasstirred and refluxed for 2.5 hours. The reaction was concentrated toabout one-tenth its volume, and water was added to the mixture,resulting in a red solution. The solution was extracted withdichloromethane, the extract washed (H₂O), dried (MgSO₄), and thesolvent was concentrated to afford 6.6 g of a rose-colored solid. Tworecrystallizations from toluene-hexane afforded 4.3 g (52%) of3-(4-methyl-1-piperazinyl)-1H-indazole as an off-white solid,m.p.=111°-113° C.

ANALYSIS: Calculated for C₁₂H₁₆N₄: 66.64% C; 7.46% H; 25.91% N; Found:66.83% C; 7.42% H; 25.69% N

(H) 4-(1H-indazol-3-yl)-1-piperazinecarbonitrile

To a stirred mixture of cyanogen bromide (5.3 g, 0.05 mol), K₂CO₃ (7.1g) and dimethylsulfoxide (40 ml) was added, dropwise,3-(4-methyl-1-piperazinyl)-1H-indazole (11.0 g, 0.051 mol) dissolved indimethylsulfoxide (60 ml). The reaction was stirred at ambienttemperature for 1 hour, and then it was poured into water. The aqueoussuspension was extracted with ethyl acetate, the ethyl acetate waswashed (H₂O), dried (MgSO₄), and concentrated to afford 7.8 g (67%) of ayellow solid. The sample was combined with another and recrystallizedtwice from toluene to afford analytically pure4-(1H-indazol-3-yl)-1-piperazinecarbonitrile as a white solid,m.p.=120°-122° C.

ANALYSIS: Calculated for C₁₂H₁₃N₅: 63.42% C; 5.76% H; Found: 63.04% C;5.84% H

(I) 3-(1-Piperazinyl)-1H-indazole

A mixture of 4-(1H-indazol-3-yl)-1-piperazinecarbonitrile (8.0 g, 40mmol) and 25% H₂SO₄ (100 ml) was stirred at reflux for 4.5 hours. Thereaction was cooled in an ice bath and made basic by the dropwiseaddition of 50% NaOH. The basic solution was extracted with ethylacetate. The ethyl acetate was washed with H₂O, dried with MgSO₄, andconcentrated to afford 5.2 g (73% of the desired compound, as a solid.The solid recrystallized twice from toluene to afford 3.0 g of3-(1-piperazinyl)-1H-indazole, m.p.=153°-155° C.

ANALYSIS: Calculated for C₁₁H₁₄N₄: 65:32% C; 6.98% H; 27.70% N; Found:65.21% C; 6.99% H; 27.80% N

(J)1-[4-[3-[4-(1H-Indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone

A mixture of 3-(1-piperazinyl)-1H-indazole (4.0 g, 20 mmol), K₂CO₃ (3.0g, 22 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22mmol), a few crystals of KI, and dimethylformamide (60 ml) was stirredat 90 C. for 5 hours. The reaction was poured into water, and theaqueous mixture was extracted with ethyl acetate. The extract was washed(brine), dried (MgSO₄), and the solvent was concentrated to afford awhite solid, which was triturated with diethyl ether and collected toyield 7.0 g of product. Two recrystallizations from absolute ethylalcohol yielded 5.3 g (64%) of analytically pure1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone,m.p.=155°-157° C.

ANALYSIS: Calculated for C₂₃H₂₈N₄O₄: 67.62% C; 6.91% H; 13.72% H; Found:67.45% C; 6.74% H; 13.56% N

EXAMPLE 21-[4-[3-[4-(1,2-Benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone

A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.8 g,20 mmol), K₂CO₃ (5.2 g, 40 mmol),1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a fewcrystals of KI and dimethylformamide (60 ml) was stirred at 90 C. for 16hours. The reaction was poured into water and the aqueous mixture wasextracted with ethyl acetate. The extract was washed (water), dried(MgSO₄) and concentrated to afford a brown oil. The oil waschromatographed on a Waters Prep 500 utilizing silica gel columns andethyl acetate-diethylamine (2%), as eluent. Concentration of theappropriate fractions afforded 3.9 g of product as an off-white solid.Recrystallization from absolute ethyl alcohol afforded 2.6 g (33%) of1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone,m.p.=102°-104° C., as colorless needles.

ANALYSIS: Calculated for C₂₄H₂₈N₂O₄: 70.56% C; 6.91% H; 6.86% N; Found:70.73% C; 6.93% H; 6.85N

EXAMPLE 31-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazolehydrochloride (5.1 g, 20 mmol), K₂CO₃ (5.2 g, 40 mmol),1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), anddimethylformamide (60 ml) was heated at 90° C. for 16 hours. Thereaction was poured into water, and the aqueous mixture was extractedwith ethyl acetate. The ethyl acetate was washed (water), dried (MgSO₄)and concentrated to afford a moist solid. Recrystallization (twice) fromethyl alcohol afforded 5.0 g (58%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanoneas a beige solid, m.p.=118°-120° C.

ANALYSIS: Calculated for C₂₄H₂₇FN₂O₄: 67.60% C; 6.38% H; 6.57% N; Found:67.47% C; 6.40% H; 6.53% N

EXAMPLE 41-[4-[4-[4-(1,2-Benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone

A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.3 g,18 mmol), K₂CO₃ (5.5 g, 40 mmol), and1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.5 g, 18 mmol), anddimethylformamide (60 ml) was stirred and heated at 75° C. for 16 hours.The reaction was poured into water and was extracted with ethyl acetate.The ethyl acetate was washed (water), dried (MgSO₄), and the solventconcentrated to afford 7.2 g of a beige solid. Recrystallization (twice)from ethyl alcohol yielded 3.3 g (43%) of1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone,m.p.=99°-101° C.

ANALYSIS: Calculated for C₂₅H₃₀N₂O₄: 71.11% C; 7.16% H; 6.63% N; Found:70.76% C; 7.24% H; 6.58% N

EXAMPLE 51-[4-[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazolehydrochloride (5.1 g, 0.02 mol), K₂CO₃ (5.2 g, 0.04 mol),1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.6 g, 22 mmol), anddimethylformamide (60 ml) was heated at 75° C. for 5 hours. The reactionwas poured into water, and the aqueous mixture was extracted with ethylacetate. The ethyl acetate was washed (water), dried (MgSO₄), and thesolvent was concentrated to yield initially an oil, which solidifiedupon standing. The solid was triturated with hexane and collected toafford 7.7 g of the product as a waxy solid. The compound waschromatographed on a Waters Prep 500 utilizing silica gel columns andeluting with dichloromethane/methanol (5%). Concentration of theappropriate fractions yielded 5.1 g of off-white solid1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone,which when recrystallized from ethyl alcohol yielded 3.2 g (36%) offeathery-white needles, m.p.=88°-90° C.

ANALYSIS: Calculated for C₂₅H₂₉FN₂O₄: 68.16% C; 6.64% H; 6.36% N; Found:67.96% C; 6.49% H; 6.29% N

EXAMPLE 61-[4-[2-[4-(1,2-Benzisoxazol-3-yl)-1-piperidinyl]-ethoxy]-3-methoxyphenyl]ethanonefumarate

A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.8 g,20 mmol), K₂CO₃ (5.2 g, 40 mmol),1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (5.0 g, 22 mmol), anddimethylformamide (90 ml) was heated at 90° C. for 16 hours. Thereaction was poured into water and the aqueous mixture was extractedwith ethyl acetate. The ethyl acetate was washed (water), dried (MgSO₄),and the solvent was concentrated to afford an oil. Upon standing, theoil solidified to afford a beige solid. The crude solid wasrecrystallized twice from ethyl alcohol to afford 5.9 g of an off-whitesolid. The solid was dissolved in ethyl acetate, and fumaric acid (1.2g, 1.1 equiv.) was added. The mixture was heated briefly on a steambath, and then stirred at ambient temperature for 2 hours. An initialgreen oil settled out and the supernatant solution was decanted. Etherwas added to the decantate and 4.0 g of a white fumarate salt wascollected. The salt was recrystallized twice from ethanol-ether to yield1.7 g (17%) of1-[4-[2-[4-(1,2-benzisoxazol-3-yl)-1piperidinyl]ethoxy]-3-methoxyphenyl]ethanonefumarate, m.p.=127°-129° C.

ANALYSIS: Calculated for C₂₃H₂₆N₂O₄.C₄H₄O₄: 63.52% C; 5.92% H; 5.49% N;Found: 63.00% C; 5.87% H; 5.42% N

EXAMPLE 71-[4-[4-[4-(1H-Indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanonefumarate

A stirred mixture of 3-(1-piperazinyl)-1H-indazole (4.0 g, 20 mmol),K₂CO₃ (5.3 g, 40 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone(6.6 g, 22 mmol), and dimethylformamide (60 ml) was heated at 75° C. for6 hours. The reaction was poured into water, and a white solidprecipitated from solution. The solid was collected and dried to afford7.2 g of the crude product. The crude solid was recrystallized twicefrom ethyl alcohol to yield 4.1 g of the free base, which was convertedto its fumarate salt by the addition of fumaric acid (1.1 g) to thecompound dissolved in refluxing acetone. The resulting fumarate salt(5.0 g) was recrystallized from ethyl alcohol to afford 3.8 g (35%) of1-[4-[4-[4-(1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanonefumarate, as a white solid, m.p.=163°-165° C.

ANALYSIS: Calculated for C₂₄H₃₀N₄O₃.C₄H₄O₄: 62.44% C; 6.36% H; 10.40% N;Found: 62.28% C; 6.62% H; 10.34% N

EXAMPLE 81-[4-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazolehydrochloride (5.1 g, 20 mmol), K₂CO₃ (5.2 g),1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (5.0 g, 1022 mmol), anddimethylformamide (90 ml) was heated at 90° C. for 16 hours. Thereaction was poured into water, and the aqueous mixture was extractedwith ethyl acetate. The ethyl acetate was washed (water), dried (MgSO₄),and concentrated to afford 7.4 g of a yellow solid. The solid waschromatographed on a Waters Prep LC 500 utilizingdichloromethane/methanol (4%) as eluent, and subsequent concentration ofthe appropriate fraction afforded 4.0 g of a yellow solid. The solid wasrecrystallized from ethyl alcohol to yield 3.1 g (38%) of1-[4-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone,as slightly yellow flakes, m.p.=132°-134° C.

ANALYSIS: Calculated for C₂₃H₂₅FN₂O₄: 66.98% C; 6.11% H; 6.79% N; Found:66.90% C; 6.20% H; 6.74% N

EXAMPLE 94-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α-methylbenzenemethanol

To a stirred mixture of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy-3-methoxy-phenyl]ethanone(4.0 g, 9.4 mmol) in methanol/tetrahydrofuran (60 ml, 1:1), was addedsodium borohydride (0.4 g, 10 mmol). After an initial evolution of gas,all insolubles went into solution. The reaction was stirred at ambienttemperature for 3 hours and TLC at this time showed a very slight amountof starting ketone. Therefore, another 0.1 g of sodium borohydride wasadded, and stirring was continued for an additional 0.5 hour. TLC nowshowed complete disappearance of starting material. The reaction wasconcentrated to an off-white residue, which was diluted with water andcollected to yield 3.4 g of alcohol. This was recrystallized fromtoluene (twice, with a charcoal treatment) to yield 2.7 g (67%) of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methoxy-α-methylbenzenemethanolas a white solid, m.p.=135°-138° C.

ANALYSIS: Calculated for C₂₄H₂₉FN₂O₄: 67.27% C; 6.82% H; 6.54% N; Found:67.59% C; 6.89% H; 6.47% N

EXAMPLE 101-[4-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone

A mixture of 3-(4-piperidinyl)-1,2-benzisothiazole (3.0 g, 13.7 mmol),potassium carbonate (2.3 g, 16.5 mmol),1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.0 g, 16.5 mmol),potassium iodide (200 mg) and acetonitrile (100 ml) was stirred atreflux under N₂ for 24 hours. The cooled reaction was filtered and thecake was washed well with acetonitrile. The filtrate was concentrated toan oily residue, which was partitioned between water and ethyl acetate.The ethyl acetate extract was washed well with water, dried with MgSO₄and concentrated to yield 6.1 g of a beige oil which solidified uponstanding. The product was triturated with diethyl ether and filtered togive 4.2 g of a beige solid. The compound was recrystallized from ethylalcohol to afford 3.5 g, and another recrystallization from ethylalcohol (utilizing decolonizing carbon) provided 2.4 g (41%) of1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone,m.p. 93°-95° C.

ANALYSIS: Calculated for C₂₄H₂₈N₂O₃S: 67.90% C; 6.65% H; 6.60% H; Found:67.89% C; 6.61% H; 6.59% N

EXAMPLE 111-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone(A) 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone

To a stirred solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone(10.0 g, 41 mmol) in methylene chloride (120 ml) cooled to −50° C. (dryice-methanol) was added, dropwise, 1M boron tribromide in methylenechloride (123 ml, 120 mmol). The temperature was kept between −40° C.and −50° C. After complete addition, the reaction was permitted to reach−30° C., and the TLC checked (ca. 15 min. after final boron tribromidewas added). Saturated NaHCO₃ was added, dropwise, never allowing thetemperature to go above 0° C. during most of the addition. Whensufficient NaHCO₃ had been added to make the solution basic, the organiclayer was collected. The layer was washed with brine, dried (MgSO₄), andconcentrated to yield 8.1 g of dark brown oil, which solidified onstanding. This was chromatographed on a Waters Prep 500 LC (2 silicacolumns, 2% methanol-methylene chloride as eluent). Upon concentrationof the appropriate fractions, 5.8 g of a brown tacky solid wereobtained. This was recrystallized from isopropyl ether (with decantingof the yellow isopropyl ether supernatant from the dark brown oilyresidue) to give initially 2.5 g of a yellow solid. Concentration of themother liquor gave an addition 0.5 g, m.p.=110°-113° C.

(B)1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8g, 13 mmol), NaHCO₃ (1.1 g), several crystals of KI,1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone, and acetonitrile (100ml) was refluxed for 16 hours. The reaction was poured into water, andthe aqueous mixture was extracted with ethyl acetate. The organicextract was washed (water), dried (MgSO₄), and the solvent wasconcentrated to afford 5.7 g of a thick yellow oil. The oil waschromatographed on a Waters Prep 500 LC on silica gel, eluting with 7%methanol/methylene chloride. Concentration of the appropriate fractionafforded a yellow oil, which upon standing yielded 3.5 g of the compoundas a pale, yellow solid. The solid was recrystailized from ethyl alcoholto afford 2.7 g (50%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]-propoxy]-3-hydroxyphenyl]ethanoneas a pale yellow solid, m.p.=122°-124° C.

ANALYSIS: Calculated for C₂₂H₂₅FN₂O₄: 66.98% C; 6.11% H; 6.79% N; Found:66.97% C; 6.20% H; 6.69% N

EXAMPLE 121-[4-[3-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole (2.3 g, 100mmol), K₂CO₃ (1.5 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone(2.8 g, 11 mmol), several crystals of KI and dimethylformamide (60 ml)was heated at 90° C. for 16 hours. The reaction was poured into H₂O, andthe aqueous suspension was extracted with ethyl acetate. The ethylacetate was washed (H₂O), dried (MgSO₄) and concentrated to afford 5.0 gof a yellow oil. The oil was chromatographed on a Waters Prep 500utilizing silica gel columns and eluting with methylenechloride/methanol (7%). Concentration of the desired fractions yielded2.0 g (46%) of an off-white solid. This sample was combined with 1.0 gof a previous sample, and this was recrystallized from toluene to afford2.6 g of1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-propoxy]-3-methoxyphenyl]ethanoneas a white solid, m.p.=135°-137° C.

ANALYSIS: Calculated for C₂₃H₂₇FN₄O₃: 64.77% C; 6.38% H; 13.14% N;Found: 64.66% C; 6.21% H; 13.02% N

EXAMPLE 131-[4-[4-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazolehydrochloride (5.0 g, 19 mmol), K₂CO₃ (5.8 g) and1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.3 g, 21 mmol) anddimethylformamide (80 ml) was heated at 75° C. for 6 hours. The reactionwas poured into water, and an off-white solid formed from solution. Thesolid was collected and dried to yield 4.5 g of crude product. Thecompound was recrystallized from ethanol (3 times) to afford 3.0 g of anoff-white solid. The solid was chromatographed on a Waters Prep 500utilizing silica gel columns and eluting with methylenechloride/methanol (7%). Concentration of the appropriate fractionsafford 2.3 g of an off-white solid, which when recrystallized fromethanol yielded 1.9 g (26%) of analytically pure1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-butoxy]3-methoxyphenyl]ethanone,m.p.=156°-158° C.

ANALYSIS: Calculated for C₂₄H₂₉FN₄O₃: 65.44% C; 6.64% H; 12.72% N;Found: 65.38% C; 6.49% H; 12.60% N

EXAMPLE 141-[4-[3-[4-(1H-Indazol-3yl)-1-piperindinyl]propoxy]-3-methoxyphenyl]ethanone

A mixture of 3-(4-piperidinyl)-1H-indazole (3.0 g, 15 mmol), K₂CO₃ (1.6g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), afew crystals of KI and acetonitrile (100 ml) was stirred and refluxedfor 16 hours. The reaction was poured into water and a white solidseparated from solution. The solid was collected, dried and afforded 5.1g of product. Recrystallization from ethanol yielded 3.6 g of thecompound, which upon chromatography (preparative HPLC on silica gel,eluting with methylene chloride/methanol-9:1) gave 3.0 g (49%) of anoff-white solid. Recrystallization from ethanol afforded theanalytically pure1-[4-[3-[4-(1H-indazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanoneas a white solid, m.p.=172°-173° C.

ANALYSIS: Calculated for C₂₄H₂₉N₃O₃: 70.74% C; 7.17% H; 10.31% H; Found:70.52% C; 7.27% H; 10.42% N

EXAMPLE 151-[4-[3-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone

A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazol (4.7 g,20 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.8 g, 20mmol), K₂CO₃ (2.8 g), several crystals of KI and acetonitrile (120 ml)was refluxed for 16 hours. The reaction was filtered and the filtratewas concentrated to yield a solid-oil mixture. The residue waschromatographed on a Waters Prep 500 utilizing silica columns andeluting with methylene chloride/methanol (5%). Concentration of thedesired fractions yielded 3.2 g of a beige solid, which uponrecrystallization from ethanol afforded 2.7 g (31%) of1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanoneas a beige solid, m.p.=116°-118° C.

ANALYSIS: Calculated for C₂₄H₂₇ClN₂O₄: 65.08% C; 6.14% H; 6.32%; Found:65.35% C; 6.22% H; 6.28% N

EXAMPLE 161-[4-[4-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone

A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7g, 20 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20mmol), K₂CO₃ (2.8 g) and acetonitrile (120 ml) was refluxed for 16hours. The reaction was allowed to cool, filtered, and the filtrate wasconcentrated to 9.9 g of a brown oil. The oil was chromatographed on aWaters Prep 500 utilizing silica gel columns and eluting with methylenechloride/methanol (5%). Concentration of the appropriate fractionsafforded 2.3 g of an off-white solid. The solid was dissolved in ethanoland fumaric acid (0.62 g, 1.1 eg.) was added. Upon concentration of theethanol, a crude, brown solid was collected, which was taken up inrefluxing acetone. Upon cooling, a white solid crystallized fromsolution yielding 2.2 g (19%) of1-[4-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanonefumarate as a white solid, m.p.=139°-141° C.

ANALYSIS: Calculated for C₂₅H₂₉ClN₂O₄.C₄H₄O₄: 60.78% C; 5.80% H; 4.89%N; Found: 60.69% C; 5.74% H; 4.85% N

EXAMPLE 171-[4-[3-[4-(5-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone

A mixture of 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2.4 g, 10 mmol),K₂CO₃ (1.4 g), a few crystals of KI and acetonitrile (100 ml) wasstirred and refluxed for 8 hours. The reaction was poured into water andthe aqueous mixture was extracted with ethyl acetate. The ethyl acetateextract was washed (brine), dried (MgSO₄), and concentrated to afford4.0 g of a white solid. The solid was chromatographed on a Waters Prep500 HPLC utilizing silica gel columns and eluting with methylenechloride/methanol (5%). Concentration of the appropriate fractionsafforded 2.0 g (47%) of1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanoneas a white crystalline solid, m.p.=103°-105° C.

ANALYSIS: Calculated for C₂₄H₂₇FN₂O₄: 67.59% C; 6.38% H; 6.57% N; Found:67.50% C; 6.47% H; 6.53% N

EXAMPLE 186-Fluoro-3-[1-[3-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazolefumarate

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.45g; 11.1 mmol), K₂CO₃ (2.0 g), and 3-(2-methoxyphenoxy)propyl chloride(3.5 g, 17.4 mmol) in acetonitrile (40 ml) was heated at 90° C. for 4hours. At the end of the reaction, the solvent was removed, and thesolids were dissolved into dichloromethane (100 ml). The solution waswashed with water and brine, then dried over MgSO₄. The crude materialfrom the solution was combined with 1.2 g of crude material prepared inthe same fashion (using 0.5 g of starting material). The combinedmaterial was purified by flash chromatography on a silica gel column (49g, eluted with 0.5% diethylamine; 1% methanol:98.5% dichloromethane, 1L). The fractions containing the pure product were pooled andconcentrated down to a light oil (3.68 g). This oil was treated withfumaric acid (1.14 g, 9.8 mmol) in ethanol (13 ml). The6-fluoro-3-[1-[3-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazolefumarate crystals obtained weighed 4.01 g (60%), m.p.=169°-170° C.

ANALYSIS: Calculated for C₂₂H₂₅FN₂O₃.C₄H₄O₄: 62.39% C; 5.84% H; 5.60% N;Found: 62.37% C; 5.88% H; 5.60% N

EXAMPLE 191-[3-[3-[4-(4-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy-4-methoxyphenyl]phenylmethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole (2.01g; 9.13 mmol), K₂CO₃ (2.0 g), and1-[3-(3-chloropropoxy)-4-methoxy-phenyl]phenylmethanone (3.93 g; 11.3mmol) and acetonitrile (50 ml) was heated at reflux for 4 hours. At theend of the reaction, the solvent was evaporated and the residue waspartitioned between water (150 ml) was dichloromethane (400 ml). Thedichloromethane solution was washed with water and brine (100 ml), driedover MgSO₄, then concentrated to an oil. The purification was done byflash chromatography over a silica gel column (SiO₂, 40 g; eluted withdichloromethane, 300 ml; 1% methanol in dichloromethane, 850 ml). Thematerial thus obtained as a colorless oil solidified on standing.Recrystallization from ethanol (150 ml) gave1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]phenylmethanoneas white crystals, 3.07 g (63%), m.p.=140°-141° C.

ANALYSIS: Calculated for C₂₉H₂₉FN₂O₄: 71.30% C; 5.98% H; 5.73% N; Found:71.09% C; 5.98% H; 5.73% N

EXAMPLE 201-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone

A mixture of 3-(4-piperidinyl)-1H-indazole (3.2 g, 16 mmol),1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.0 g, 16 mmol), K₂CO₃(2.2 g) and acetonitrile (100 ml) was stirred and refluxed for 6 hours.The reaction was poured into water and the resulting yellow solid thatformed was collected to afford 5.3 g of product. The compound wasrecrystallized from acetonitrile and then from ethyl acetate to yield3.0 g (45%) of a slightly yellow solid of1-[4-[4-[4-(1H-indazol-3-yl)-1piperidinyl]-butoxy]-3-methoxyphenyl]ethanone,m.p.=133°-135° C.

ANALYSIS: Calculated for C₂₅H₃₁N₃O₃: 71.23% C; 7.41% H; 9.97% N; Found:70.85% C; 7.61% H; 9.81% N

EXAMPLE 211-[4-[2-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2 benzisoxazole (4.6g, 19 mmol), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (4.3 g, 19mmol), K₂CO₃ (2.8 g), a few crystals of KI and acetonitrile (120 ml) wasrefluxed for 16 hours. The reaction was filtered and the filtrate wasconcentrated to yield 8.0 g of yellow solid. The solid waschromatographed on a Waters Prep 500 LC (silica columns, eluting withmethylene chloride/methanol, 5%). Concentration of the appropriatefractions yielded 3.2 g of a light yellow solid, which uponrecrystallization from ethyl acetate afforded 2.3 g (28%) of1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanoneas a pale yellow solid, m.p.=133°-135° C.

ANALYSIS: Calculated for C₂₃H₂₅ClN₂O₄: 64.41% C; 5.88% H; 6.53% N;Found: 64.35% C; 5.87% H; 6.41% N

EXAMPLE 22 3-(3-Bromopropoxy-4-methoxyphenyl)phenylmethanone

A solution of 3-hydroxy-4-methoxybenzophenone (4.6 g, 20 mmol) indimethyl formamide (35 ml) was treated with sodium hydride (600 mg, 25mmol) at 0° C. for 20 minutes, then 1,3-dibromopropane (5 g, 24.7 mmol)was added in one portion. The mixture was heated at 90° C. for 1 hour,and then stirred at room temperature for 2 hours. At the end of thereaction, the mixture was poured into water (500 ml) and extracted withethyl acetate (400 ml). The ethyl acetate solution was washed withwater, brine and dried over anhydrous MgSO₄. The solvent was removed andthe crude oil was purified by flash chromatography over a silica gelcolumn (SiO₂, 85 g; eluted with 3:1 hexane:dichloromethane, 1.6 l; 3.7hexane:dichloromethane, 1.4 l). The pure product thus obtained weighed4.67 g, (66%) as an oil. Recrystallization twice from isopropyl ether(500 ml) gave analytically pure3-(3-bromopropoxy-4-methoxyphenyl)phenylmethanone (2.42 g), m.p.=81°-83°C.

ANALYSIS: Calculated for C₁₇H₁₇BrO₃: 58.47% C; 4.91% H; Found: 58.63% C;4.82% H

EXAMPLE 231-[3-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanonefumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride(4.53 g, 20.5 mmol), K₂CO₃ (4.5 g),1-[3-(3-chloropropoxy)phenyl]ethanone (6.4 g 29 mmol) in acetonitrile(60 ml) was heated at reflux for 5 hours. At the end of the reaction,the solvent was removed and the residue was extracted intodichloromethane (300 ml). The inorganic insolubles were filtered off.The dichloromethane solution was concentrated to a small volume (10 ml)and purified on a flash chromatographic column (SiO₂, 75 g, eluted withdichloromethane, 900 ml; and 2% methanol in dichloromethane, 800 ml).The fractions containing the pure product were combined and concentratedto an oil (2.87 g, 35%). The oil was dissolved into ethanol and treatedwith a solution of fumaric acid (841 mg). Recrystallization (twice) fromethanol afforded 2.53 g of1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanonefumarate as white crystals, m.p.=172°-174° C.

ANALYSIS: Calculated for C₂₂H₂₅FN₂O₃.C₄H₄O₄: 63.27% C; 5.70% H; 5.47% N;Found: 63.00% C; 5.63% H; 5.43% N

EXAMPLE 241-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methylphenyl]-ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazolehydrochloride (5.5 g, 21.6 mmol), K₂CO₃(3.5 g),1-[4-(3-bromopropoxy)-2-methylphenyl]-ethanone (4.83 g, 17.8 mmol) indimethylformamide (25 ml) and acetonitrile (75 ml) was heated at 120° C.for 5 hours. At the end of the reaction, the solvent was removed and theresidue was extracted into dichloromethane (300 ml) and the solution waswashed with water and brine. The organic solution was dried andevaporated to a crude oil. The purification was done by flashchromatography over a silica gel column (80 g, eluted withdichloromethane, 1 l; 1% methanol:dichloromethane, 1.2 l; 2%methanol:dichloromethane, 1.2 l). The purest fractions were combined andafforded 2.91 g of solid. Recrystallization from dichloromethane andethanol gave 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methylphenyl]ethanone as off-white crystals: 2.42 g,m.p.=113°-114° C.

ANALYSIS: Calculated for C₂₄H₂₇FN₂O₃: 70.22% C; 6.63% H; 6.82% N; Found:70.13% C; 6.63% H; 6.77% N

EXAMPLE 251-[2-[3-[4-(6Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]5-methylphenyl]-ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride(2.87 g, 11.23 mmol), K₂CO₃ (2.5 g),1-[2-(3-bromopropoxy)-5-methylphenyl]ethanone (3.74 g, 13.8 mmol) indimethylformamide (10 ml) and acetonitrile (50 ml) was heated at 95° C.for 6 hours. At the end of the reaction, the solvent was concentratedand the mixture was extracted into dichloromethane (300 ml). The organicsolution was washed with water and brine, dried over MgSO₄, thenconcentrated down to a crude oil. The purification was done by flashchromatography over a silica gel column (SiO₂, 60 g, eluted with 1%C;H₃OH:dichloromethane: 1.2 l; 3% CH₃OH:dichloromethane: 600 ml). Thematerial thus obtained was crystallized from a small volume of ether andhexane to provide 2.13 g (46%) of off-white1-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-iperidinyl]propoxy]-5-methylphenyl]ethanone,m.p.=92°-93° C.

ANALYSIS: Calculated for C₂₄H₂₇FN₂O₃: 70.22% C; 6.63% H; 6.82% N; Found:70.21% C; 6.69% H; 6.81% N

EXAMPLE 26N-[3-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]acetamide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride(3.94 g, 15.4 mmol), K₂CO₃ (3.67 g, 26.6 mmol),N-[3-(3-bromopropoxy)-4-methoxyphenyl] acetamide (5.56 g, 18.6 mmol) indimethylformamide (75 ml) and acetonitrile (100 ml) was heated at 100°C. for 3 hours. At the end of the reaction, the solvent was concentratedand the mixture was extracted into dichloromethane (500 ml). The organicsolution was washed with water (500 ml) and brine (400 ml), dried, thenconcentrated to a crude oil. The purification was effected by flashchromatography over a silica gel column (SiO₂, 65 g, eluted with 1%CH₃OH:dichloromethane, 1.2 l; and 3% C;H₃OH:dichloromethane, 500 ml).The material thus obtained weighed 2.33 g (34.3%) as an oil. Thismaterial was dissolved in ethanol and treated with a solution of fumaricacid (661 mg) in ethanol. The N-[3-[3-[4-(6-fluoro-1,2benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl] acetamidehemifumarate was obtained as off-white crystals weighing 2.17 g,m.p.=205°-206° C.

ANALYSIS: Calculated for C₂₄H₂₈FN₃O₄.0.5 C₄H₄O₄: 62.50% C; 6.05% H;8.41% N; Found: 62.30% C; 6.05% H; 8.32% N

EXAMPLE 27 6-Chloro-3-(1-piperazinyl)-1H-indazole

To a stirred suspension of4-(6-chloro-1-phenylsulfonyl-1H-indazol-3-yl)-1-piperazinecarbonitrile(192.5 g, 479 mmol) in dry tetrahydrofuran (3.5 l) under N₂ was added,dropwise, LiAlH₄ (958 ml of a 1.0M solution of lithium aluminum hydridein tetrahydrofuran; 958 mmol). After complete addition, the reaction washeated to reflux and stirred under N₂ for 4 hours. The reaction wascooled to 4° in an ice-salt bath and the excess lithium aluminum hydridewas destroyed by the careful, dropwise addition of H₂O. The mixture wasstirred vigorously for an addition 30 minutes and was then filteredthrough a course sintered glass funnel. The filter cake was washed wellwith tetrahydrofuran (3×500 ml) and then with methanol (2×500 ml) andthe filtrate was concentrated to yield 151.0 g of a beige gum.Trituration with diethyl ether afforded a solid, which was collected anddried to give 75.0 g (66%) of the desired indazole. A 4.0 g sample wasrecrystallized from toluene to yield 3.2 g, which was recrystallizedagain from toluene (utilizing decolonizing carbon) to provide 2.1 g(35%) of a beige, 6-chloro-3-(1-piperazinyl)-1H-indazole solid,m.p.=135°-137° C.

ANALYSIS: Calculated for C₁₁H₁₃ClN₄: 55.82% C; 5.54% H; 23.67% N; Found:55.91% C; 5.54% H; 23.41% N

EXAMPLE 281-[4-[3-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (3.5 g, 16mmol), K₂CO₃ (2.2 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone(3.8 g, 16 mmol) acetonitrile (90 ml) was refluxed for 16 hours. Thereaction was poured into water and the resulting white solid, whichprecipitation from solution, was collected to afford 5.5 g of thedesired product. The compound was recrystallized from dimethylformamide(twice) to afford 3.0 g (44%) of1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]ethanoneas a white solid, m.p.=202°-204° C.

ANALYSIS: Calculated for C₂₄H₂₈FN₃O₃: 67.75% C; 6.63% H; 9.88% N; Found:67.59% C; 6.61% H; 9.96% N

EXAMPLE 291-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methylphenyl]-ethanonehemifumarate

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazolehydrochloride (3.0 g; 11.7 mmol), K₂CO₃ (3.0 g), and1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone (3.19 g) indimethylformamide (20 ml) and acetonitrile (50 ml) was heated at 95° C.for 4 hours. At the end of the reaction, the solvent was concentrateddown to about 30 ml, then partitioned between water (200 ml) anddichloromethane (300 ml). The dichloromethane solution was separated andwashed with water and brine, then dried over MgSO₄. The crude productfrom the evaporated solution was purified by flash chromatography over asilica gel column (SiO₂, 60 g, eluted with 1% methanol indichloromethane, 600 ml; 2% methanol in dichloromethane, 600 ml). Thematerial thus obtained with a light yellow oil, weight: 2.07 g (43%).This oil was dissolved in ethanol and treated with a solution of fumaricacid (585 mg) in ethanol. The1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methylphenyl]ethanonehemifumarate crystals formed on cooling at 0° C. This was collected andweighed 1.5 g, m.p.=185°-187° C.

ANALYSIS: Calculated for C₂₄H₂₇FN₂O₃.0.5 C₄H₄O₄: 66.65% C; 6.24% H;5.98% N; Found: 66.69% C; 6.23% H; 5.95% N

EXAMPLE 301-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.27 g, 14.8mmol), K₂CO₃ (3 g), 1-[4-(3-bromopropoxy)phenyl]ethanone (4.5 g, 17.5mmol) in acetonitrile (60 ml) was heated at reflux for 4 hours. Thesolvent was removed. The residue was dissolved in dichloromethane (300ml) and washed with water and brine, then dried over MgSO₄. The crudeproduct from the evaporated solution was purified by flashchromatography (SiO₂, 60 g; eluted with 1% methanol in dichloromethane,1 liter). The purest fractions were combined and gave 2.8 g, 48%, of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy)phenyl]ethanone,m.p.=111°-112° C.

ANALYSIS: Calculated for C₂₃H₂₅FN₂O₃: 69.68% C; 6.36% H; 7.07% N; Found:69.80% C; 6.38% H; 7.07% N

EXAMPLE 311-[4-[3-[4-(6-Chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanone

A mixture of 6-chloro-3-(1-piperazinyl)-1H-indazole (3.4 g, 14 mmol),K₂CO₃ (2.5 g, 18 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone(3.8 g, 16 mmol), KI (200 mg), and acetonitrile (125 ml) was stirred atreflux under N₂ for 30 hours. After standing at room temperature for 40hours, the reaction was filtered and the filter cake was washed wellwith acetonitrile. The filtrate was concentrated to an oily solid, whichwas partitioned between water and ethyl acetate. The ethyl acetateextract was washed with water, dried with MgSO₄, and concentrated toyield 6.9 g of a dark oil, which solidified after 2 days under vacuum.The product was purified by preparative HPLC (Waters Associates PrepLC/system 500 utilizing 2 silica gel columns and 6% methanol/methylenechloride as eluent) to yield 4.2 g. The material was recrystallized fromethanol to yield 3.4 g of glistening, beige,1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanonecrystals, m.p.=132°-134° C.

ANALYSIS: Calculated for C₂₃H₂₇ClN₄O₃: 62.73% C; 6.14% H; 12.65% N;Found: 62.49% C; 6.16% H; 12.60% N

EXAMPLE 321-[4-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone

A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol),1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20.0 mmol), K₂CO₃(3.0 g, 21.8 mmol), KI (200 mg), and acetonitrile (125 ml) was stirredat reflux under N₂ for 5 hours. Most of the solvent was removed in vacuoand the resultant gummy residue was partitioned between ethyl acetateand water. The organic extract was washed with water, dried with MgSO₄,and concentrated to yield 7.8 g. Purification by preparative HPLC(Waters Associates Prep LC/System 500, utilizing 2 silica gel columnsand 4% methanol-methylene chloride as eluent) afforded 6.5 g of a damp,off-white solid. The product was recrystallized twice from toluene toprovide 3.1 g (39%) of1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanoneas a white solid, m.p.=114°-116° C.

ANALYSIS: Calculated for C₂₄H₂₉N₃O₃S: 65.58% C; 6.65% H; 9.56% N; Found:65.74% C; 6.66% H; 9.54% N

EXAMPLE 334-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzonitrile

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6mmol), K₂CO₃ (2.8 g), 4-(3-bromopropoxy)-3-methoxybenzonitrile (4.0 g,14.8 mmol) in acetonitrile (70 ml) was heated at reflux for 3 hours. Atthe end of the reaction, the solvent was removed on a rotary evaporator.The organic material was extracted into dichloromethane (250 ml) and theinorganics were filtered off. The dichloromethane solution wasconcentrated to a crude oil. The purification was done by flashchromatography over a silica gel column (SiO₂, 55 g; eluted withdichloromethane, 600 ml; 1% methanol in dichloromethane, 600 ml). Thematerial thus obtained was crystallized from a small amount ofdichloromethane. Recrystallization from ethanol (25 ml) provided 3.8 g(68%) of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzonitrileas white crystals, m.p.=107°-108° C.

ANALYSIS: Calculated for C₂₃H₂₄FN₃O₃: 67.47% C; 5.91% H; 10.26% N;Found: 67.32% C; 5.90% H; 10.24% N

EXAMPLE 341-[4-[4-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (1.9 g, 8.6mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (2.6 g, 8.6 mmol),K₂CO₃ (1.2 g), and acetonitrile (75 ml) was refluxed for 6 hours. Thereaction was poured into water and a white solid settled from solution.This was collected, dried and afforded 3.2 g of product. The product wasrecrystallized from ethanol to yield 2.7 g (71%) of1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]butoxy]-3-methoxy-phenyl]ethanoneas glistening white flakes, m.p.=158°-160° C.

ANALYSIS: Calculated for C₂₅H₃₀FN₃O₃: 68.32% C; 6.88% H; 9.56% N; Found:68.00% C; 6.93% H; 9.51% N

EXAMPLE 351-[4-[3-[4-(1-Benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxy-phenyl]ethanonesesquifumarate

A mixture of1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone(3.2 g, 7.5 mmol) and benzoyl chloride (15 ml) was heated on a steambath for 15 minutes. The reaction was allowed to cool and ether wasadded. The insoluble off-white compound was harvested to yield 4.4 g ofthe product as a hydrochloride salt. The salt was converted to free basewith aqueous ammonium hydroxide, and after extractive workup withmethylene chloride, 3.0 g of the free base was isolated as a whitesolid. The free base was dissolved in ethyl acetate and fumaric acid(0.72 g, 1.1 eq.) was added and the mixture heated on the steam bath for15 min. After standing at ambient temperature for 4 days, 2.0 g of anoff-white fumarate salt was collected, while concentration of thefiltrate afforded an additional 1.0 of the salt. Recrystallization,first from ethyl acetate, and then from ethanol yielded 1.4 g (26%) of1-[4-[3-[4-(1-benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone sesquifumarate, m.p.=138°-140° C.

ANALYSIS: Calculated for C₃₀H₃₁FN₄O₄.1.5 C₄H₄O₄: 61.35% C; 5.29% H;7.95% N; Found: 61.68% C; 5.31% H; 8.25% N

EXAMPLE 361-[4-[4-[4-(6-Chloro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]-ethanone

A mixture of 6-chloro-[3-(1-piperazinyl)]-1H-indazole (4.0 g, 17 mmol),K₂CO₃ (2.8 g, 20 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone(5.7 g, 19 mmol), KI (100 mg) and acetonitrile (125 ml) was stirred atreflux under nitrogen for 18 hours. The cooled reaction was poured intowater and the resultant off-white solid was collected by filtration anddried to yield 7.0 g. The compound was recrystallized twice from tolueneto yield 6.2 g. Further purification by preparative HPLC (WatersAssociates Prep LC/System 500, utilizing 5% methanol/methylene chlorideas eluent and 2 silica gel columns) afforded 5.3 g of glistening, beigecrystals, which were recrystallized four times from toluene to yield 3.1g of a white solid. Analytically pure material was obtained by asubsequent recrystallization from dimethylformamide to afford 2.5 g(32%) of1-[4-[4-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanoneas an off-white powder, m.p.=189°-191° C.

ANALYSIS: Calculated for C₂₄H₂₉ClN₄O₃: 63.08% C; 6.40% H; 12.26% N;Found: 62.86% C; 6.57% H; 12.49% N

EXAMPLE 371-[4-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanonehemifumarate

A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol),K₂CO₃ (3.0 g, 21.8 mmol), KI (200 mg),1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 20.0 mmol), andacetonitrile (125 ml) was stirred at reflux under N₂ for 26 hours. Thecooled reaction was filtered and the filter cake was washed well withacetonitrile. The filtrate was concentrated to afford 10.7 g of an oilyresidue, which was extracted with ethyl acetate. The ethyl acetateextract was washed with water, dried with MgSO₄ and concentrated toyield 8.0 g of a dark oil. The oil was purified by preparative HPLC(Waters Associates Prep LC/System 500, utilizing 2 silica gel columnsand 3% methanol/methylene chloride as eluent). Concentration ofappropriate fractions provided 4.6 g of a red oil, which solidified uponstanding. A 3.4 g sample was taken up in ethyl acetate (100 ml) andfumaric acid (0.95 g) was added. The mixture was stirred at a mildreflux for 1 hour and then at ambient for 1.5 hours. The resultant beigesolid was collected by filtration and dried to yield 4.0 g. The productwas recrystallized twice from ethanol to provide 2.7 g (27%) of1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanonehemifumarate as a beige powder, m.p.=186°-188° C.

ANALYSIS: Calculated for C₂₃H₂₇N₃O₃S.0.5C₄H₄O₄: 62.09% C; 6.06% H; 8.69%N; Found: 62.01% C; 6.06% H; 8.68% N

EXAMPLE 381-[3,5-Dibromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-phenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0g, 9.0 mmol), K₂CO₃ (1.3 g), and1-[4-(3-bromopropoxy)-3,5-dibromophenyl]ethanone (2.65 g, 9.0 mmol) andacetonitrile (50 ml) was heated at reflux for 3 hours. At the end of thereaction, the solvent was evaporated and the residue was extracted intodichloromethane (150 ml). The insolubles were filtered off. Thedichloromethane solution was concentrated down to an oil. Thepurification was done by flash chromatography on a silica gel column(SiO₂, 47 g; eluted with dichloromethane, 300 ml; 1% methanol indichloromethane, 600 ml). The material thus purified as a colorless oil,solidified on standing. Recrystallization from ethanol gave1-[3,5-dibromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanoneas white crystals (2.93 g, 57%), m.p.=102°-103° C.

ANALYSIS: Calculated for C₂₃H₂₃Br₂FN₂O₃: 49.84% C; 4.18% H; 5.05% N;Found: 49.91% C; 4.11% H; 4.98% N

EXAMPLE 391-[4-[2-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]ethoxy-3-methoxyphenyl]-ethanone

A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol),1-[4-(2-chloroethoxy)-3-methoxyphenyl]-ethanone (4.3 g, 20.0 mmol),K₂CO₃ (3.0 g 21.8 mmol), acetonitrile (125 ml) and a catalytic amount ofKI was heated to reflux and stirred under nitrogen for 24 hours. At thispoint, an additional amount of K₂CO₃ (1.0 g, 7.2 mmol) and alkylatingagent (0.4 g, 1.7 mmol) was added to the reaction mixture and heating atreflux was resumed for 24 hours. The reaction was cooled to ambienttemperature and filtered. The filter cake was washed with acetonitrileand the filtrate was concentrated to afford a dark oil. The oil wasextracted with methylene chloride, and the organic extract was washedwith water, dried with MgSO₄ and concentrated to yield 9.2 g of an oil.Purification by preparative HPLC (Waters Associates Prep LC/System 500utilizing 2 silica gel columns and 3% methanol/methylene chloride aseluent) provided 3.8 g of a soft, beige gum, which readily solidified.The compound was recrystallized twice from ethanol to give 2.1 g (28%)of1-[4-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]ethanoneas a beige solid, m.p.=98°-100° C.

ANALYSIS: Calculated for C₂₂H₂₅N₃O₃S: 64.21% C; 6.12% H; 10.21% N;Found: 64.05% C; 6.09% H; 10.12% N

EXAMPLE 406-Fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.0 g, 18.2mmol), K₂CO₃ (3.0 g, 21.8 mmol), KI (100 mg), 3-chloropropoxybenzene(3.4 g, 20.0 mmol), and acetonitrile was stirred at reflux undernitrogen for 30 hours. The reaction was poured into water and theaqueous mixture was extracted with ethyl acetate. The ethyl acetateextract was washed with brine, dried with MgSO₄ and concentrated toafford 6.2 g of a damp, beige solid. The compound was recrystallizedtwice from ethanol to yield (47%) of6-fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole as alight beige solid, m.p.=78°-80° C.

ANALYSIS: Calculated for C₂₁H₂₃FN₂O₂: 71.17% C; 6.54% H; 7.90% N; Found:71.00% C; 6.52% H; 7.81% N

EXAMPLE 411-[4-[2-[4-(6-Chloro-1H-indazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]-ethanone

A mixture of 6-chloro-[3-(1-piperazinyl)-1H-indazole (2.1 g, 8.9 mmol),K₂CO₃ (1.5 g, 10.7 mmol), KI (100 mg),1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (2.2 g, 9.8 mmol) andacetonitrile (70 ml) was stirred at reflux for 48 hours under N₂. Thecooled reaction was poured into water and the aqueous mixture wasextracted with ethyl acetate. The organic extract was washed with water,dried with MgSO₄ and concentrated to yield 6.0 of a light yellow oil.The oil was purified by preparative HPLC (Waters Associates prepLC/System 500, employing 2 silica gel columns and 5.5%methanol/methylene chloride as eluent). Concentration of later fractionsprovided 1.6 g of an off-white solid. This was combined with an additionsample (3.4 g total) and two consecutive recrystallizations from ethanolyielded 2.1 g (23%) of1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]ethanoneas an off-white solid, m.p.=154°-156° C.

ANALYSIS: Calculated for C₂₂H₂₅ClN₄O₃: 61.65% C; 5.88% H; 13.06% N;Found: 61.66% C; 5.87% H; 13.06% N

EXAMPLE 421-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]-2,2,2-trifluoroethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.5 g, 6.7mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone(2.0 g, 6.7 mmol), K₂CO₃ (0.88 g), KI (0.1 g) and acetonitrile (50 ml)was stirred and refluxed for 16 hours. After cooling, the reaction waspoured into water and the aqueous mixture extracted with ethyl acetate.The extract was washed (H₂O), dried (MgSO₄), and the solvent wasconcentrated to an oil, which upon evacuation at high vacuum afforded3.2 g of a waxy solid. The solid was chromatographed on a Waterspreparative LC (silica columns, eluting with 3%methanol-dichloromethane). Concentration of the appropriate fractionsgave 1.8 g (56%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-2,2,2-trifluoroethanonesolid, m.p.=94°-96° C.

ANALYSIS: Calculated for C₂₄H₂₄F₄N₂O₄: 60.00% C; 5.03% H; 5.83% N;Found: 60.01% C; 5.06% H; 5.68% N

EXAMPLE 431-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl]-1-piperidinyl]propoxy]-3-methyl-mercaptophenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.88g, 8.5 mmol), K₂CO₃ (1.8 g) and1-[4-(3-bromopropoxy)-3-methylmercaptophenyl]ethanone (2.3 g, 7.6 mmol)in acetonitrile (100 ml) was heated at reflux for 4 hours. At the end ofthe reaction, the solvent was concentrated, then diluted withdichloromethane (250 ml). The insolubles were filtered off. Thedichloromethane solution was concentrated to dryness as an oil.Purification was effected by flash chromatography on a silica gel column(SiO₂, 54 g, eluted with dichloromethane, 500 ml; 1%methanol-dichloromethane, 1.1 l). The purest fractions were combined togive a colorless oil which solidified to an off-white solid (2.4 g).Recrystallization from ethanol (100 ml) yielded1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl]-1-piperidinyl]propoxy]-3-methylmercaptophenyl]ethanoneas off-white needle crystals, 2.15 g, m.p.=150°-152° C.

ANALYSIS: Calculated for C₂₄H₂₇FN₂O₃S: 65.14% C; 6.15% H; 6.33% N;Found; 65.09% C; 6.10% H; 6.25% N

EXAMPLE 44 1-[4-(3-Bromopropoxy)-3-bromophenyl]ethanone

A stirred mixture of 3-bromo-4-hydroxyacetophenone (4.5 g, 21.2 mmol),K₂CO₃ (4 g) and 1,3-dibromopropane (7.6 g) in acetonitrile (200 ml) washeated at reflux for 2 hours. At the end of the reaction, the solventwas removed and the residue was dissolved in dichloromethane (400 ml)and filtered. The dichloromethane solution was concentrated to an oil.The oil was added to isopropyl ether and stirred to causecrystallization (4.1 g; 58%). The solid was recrystallized fromisopropyl ether to give 3.5 g of1-[4-(3-bromopropoxy)-3-bromophenyl]ethanone as glistening crystals,m.p.=83°-84° C.

ANALYSIS: Calculated for C₁₁H₁₂Br₂O₂: 39.31% C; 3.60% H; Found: 39.80%C; 3.55% H

EXAMPLE 45 1-[4-(3-Bromopropoxy)-3,5-dibromophenyl]ethanone

A stirred mixture of 3,5-dibromo-4-hydroxyacetophenone (3.0 g, 10.1mmol), K₂CO₃ (2.8 g, 20.3 mmol), 1,3-dibromopropane (4.0 g, 19.8 mmol)in acetonitrile (100 ml) was heated at reflux for 5 hours. The solventwas removed. The crude product was extracted into dichloromethane (150ml) and the insoluble inorganics were filtered off. The solution wasconcentrated to dryness again. Purification was carried out by flashchromatography on silica gel (45 g, SiO₂; eluted with 1:1hexane:dichloromethane). The material thus obtained (2.8 g) wasrecrystallized twice from isopropyl ether to give analytically pure1-[4-(3-bromopropoxy)-3,5-dibromophenyl]ethanone, m.p.=87°-88° C.

ANALYSIS Calculated for C₁₁H₁₁Br₃O₂: 31.84% C; 2.67% H; Found: 31.97% C;2.63% H

EXAMPLE 461-[4-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 3-(4-piperidinyl)-1,2-benzisothiazole (2.6 g, 11.9mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (3.9 g, 13.1 mmol),K₂CO₃ (2.0 g, 14.3 mmol), KI (200 mg) and acetonitrile (125 ml) wasstirred at reflux under nitrogen for 18 hours. The reaction was cooledto ambient temperature and filtered. The filter cake was washed wellwith fresh acetonitrile and the filtrate was concentrated to yield awet, brown solid. The residue was diluted with water and the aqueoussuspension was extracted with methylene chloride. The organic extractwas washed with water, dried with MgSO₄ and concentrated to afford 6.5 gof a dark oil. The oil was purified by preparative HPLC (WatersAssociates prep LC/System 500, utilizing 2 silica gel columns and 5%methanol/methylene chloride) to give 4.5 g of a beige solid. A 3.1 g 7.1mmol) sample was taken up in absolute ethanol (80 ml) and oxalic acid(0.67 g, 7.4 mmol) was added. The solution was refluxed mildly on asteam bath for 45 minutes and was then stirred at ambient temperaturefor 1 hour. The resultant suspension was diluted with anhydrous ether(150 ml) and stirred for 5 minutes. The solid was collected and dried toafford 3.1 g of a light, beige solid. The salt was recrystallized fromethanol to yield 2.8 g. The compound was converted back to the free basewith 50% NaOH to give 2.4 g, which was immediately recrystallized fromethanol to provide 1.5 g (29%) of1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanoneas a beige powder, m.p.=78°-80° C.

ANALYSIS: Calculated for C₂₅H₃₀N₂O₃S: 68.46% C; 6.91% H; 6.39% N; Found:68.34% C; 6.85% H; 6.33% N

EXAMPLE 471-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-phenylmethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10mmol), K₂CO₃ (2.3 g) and1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone (3.47 g, 10 mmol)in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end ofreaction, the acetonitrile was concentrated and the mixture wasextracted into dichloromethane (200 ml). The insolubles were filteredoff and the solvent was evaporated to an oil. Purification was carriedout by flash chromatography over a silica gel column (SiO₂, 50 g; elutedwith dichloromethane, 600 ml; 1% methanol:dichloromethane, 600 ml; 2%methanol; 98% dichloromethane, 600 ml). The fractions containing thepure product were combined and concentrated to give 4.24 g (87%) of anoff-white solid. Recrystallization from ethanol (75 ml) gave 3.9 g of1-[4-[3-[4-(6-fluoro-1,2-benziosoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]phenylmethanoneas off-white crystals, m.p.=128°-130° C.

ANALYSIS: Calculated for C₂₉H₂₉FN₂O₄: 71.30% C; 5.98% H; 5.73% N; Found:71.31% C; 5.99% H; 5.57N

EXAMPLE 481-[4-[3-[4-(6-Fluoro-1,2-benziosoxazol-3-yl)-1-piperidinyl]propoxy]-3-bromophenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.1 g, 9.5mmol), K₂CO₃ (2.0 g) 1-[3-bromo-4-(3-bromopropoxy)phenyl]ethanone (3.1g, 9.2 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours.At the end of reaction, the solvent was concentrated and the mixture wasextracted into dichloromethane (200 ml). The insolubles were filteredoff. The dichloromethane was concentrated again. The crude residue waspurified by flash chromatography over a silica gel column (SiO₂, 40 g;eluted with dichloromethane, 500 ml; 1% methanol:dichloromethane, 600ml; 3% methanol; 97% dichloromethane, 600 ml). The material thusobtained (3.26 g, 72%) was recrystallized from ethanol (40 ml) to give1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-bromophenyl]ethanoneas light yellow crystals (3.0 g), m.p.=126°-128° C.

ANALYSIS: Calculated for C₂₃H₂₄BrFN₂O₃: 58.12% C; 5.09% H; 5.89% N;Found: 57.64% C; 5.35% H; 5.55N

EXAMPLE 493-[1-[3-[4-(1-Ethoxyethyl)-2-methoxyphenoxy]-propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride

To a mixture of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α-methylbenzenemethanol(3.8 g, 89 mmol) in pyridine (25 ml) was added acetic anhydride (5 ml).The mixture was warmed briefly on the steam bath to effect solution, andthen the reaction was allowed to stand at ambient temperature for 16hours. Most of the pyridine was evaporated under reduced pressure andthe resultant oil was diluted with water. The aqueous solution was madebasic with dilute NaOH, and subsequently extracted with ethyl acetate.The organic extract was washed (water), dried (MgSO₄), and the solventconcentrated to give 3.7 g of the O-acetyl derivative as a colorlessoil. The compound was dissolved in diethyl ether and ethereal HCl wasadded to precipitate a gum-like hydrochloride salt, which upon treatmentwith refluxing ethyl acetate afforded 3.4 g of a crystalline salt,m.p.=143°-145° C. Attempting to recrystallize the salt fromethanol:diethyl ether resulted in displacement of the acetate to affordthe ethyl ether. The salt of this product (2.8 g) was recrystallizedfrom ethanol:diethyl ether to yield 2.1 g (48%) of3-[1-[3-[4-(1-ethoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride, m.p.=139°-141° C.

ANALYSIS: Calculated for C₂₆H₃₃FN₂O₄.HCl: 63.34% C; 6.95% H; 5.68% N;Found: 63.06% C; 6.80% H; 5.63N

EXAMPLE 503-[1-[3-[4-(1-Acetoxyethyl)-2-methoxyphenoxy]-propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolefumarate

A mixture of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methoxy-α-methylbenzenemethanol(4.8 g, 11 mmol) in pyridine (45 ml) was warmed briefly to effectsolution and then acetic anhydride (6.3 ml) was added. The reactionstood at ambient temperature for 16 hours, was concentrated in vacuo,and the colorless oil that remained was dissolved in water. The aqueoussolution was made basic with saturated K₂CO₃ solution, and the mixturewas extracted with diethyl ether. The extract was washed (water), dried(MgSO₄) and concentrated to afford 5.2 g of a thick colorless oil. Theoil (4.8 g) was dissolved in anhydrous diethyl ether and fumaric acid(1.2 g, 0.01 mol) was added. The mixture was stirred at ambienttemperature for 4 hours, and then was permitted to stand at ambienttemperature for 16 hours. The resultant white,3-[1-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolefumarate was collected and afforded 3.0 g of material. The filtrate wastreated with an additional amount of fumaric acid (0.3 g) and 0.9 g moreof3-[1-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolefumarate was harvested. The two batches were combined and recrystallizedfrom acetonitrile (twice) to yield 2.3 g (43%) of the acetate,m.p.=150°-152° C.

ANALYSIS: Calculated for C₂₆H₃₁FN₂O₃.C₄H₄O₄: 61.43% C; 6.01% H; 4.78% N;Found: 61.06% C; 5.87% H; 4.73N

EXAMPLE 511-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]pentanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10mmol), K₂CO₃ (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]pentanone (3.7g, 11.3 mmol) acetonitrile (140 ml) was heated at reflux for 4 hours. Atthe end of the reaction, the mixture was cooled and filtered. Thefiltrate was concentrated to an oil. Purification was performed by flashchromatography over a silica gel column (SiO₂, 55 g; eluted with 1%methanol in dichloromethane, 600 ml; 3% methanol; 97% dichloromethane,400 ml). The fractions containing pure product were pooled andconcentrated to a solid (4.3 g, 91%). Recrystallization from ethanol (10ml) gave a powdery solid of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]pentanone(3.22 g), m.p.=79°-80° C.

ANALYSIS: Calculated for C₂₇H₃₃FN₂O₄: 69.21% C; 7.10% H; 5.98% N; Found:69.00% C; 6.94% H; 6.39N

EXAMPLE 522-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-N-methyl-benzenaminehemifumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.4mmol), K₂CO₃ (1.8 g, 13.0 mmol),4-(3-chloropropoxy)-2-methylaminobenzene (2.4 g, 12.0 mmol) andacetonitrile (100 ml) was stirred at reflux for 18 hours. The reactionwas cooled to ambient temperature and was poured into water. The aqueousmixture was extracted with ethyl acetate and the ethyl acetate extractwas washed with water, dried with MgSO₄, and concentrated to yield 4.1 gof a brown oil. The oil was purified by preparative HPLC (WatersAssociates prep LC/System 500, utilizing 2 silica gel columns andeluting with 4% methanol-methylene chloride). Concentration ofappropriate fractions yielded 2.45 g of a beige oil. The product wastaken up in ethyl acetate (50 ml) and fumaric acid (0.78 g) was added.The mixture was stirred at mild reflux for 45 minutes and then atambient temperature for 1.5 hours. The product was isolated by vacuumfiltration to provide 2.5 g of a pale yellow solid. Recrystallizationfrom ethanol afforded 2.0 g (40%) of2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-N-methylbenzenaminehemifumarate as beige crystals, m.p.=180°-182° C.

ANALYSIS: Calculated for C₂₂H₂₆FN₃O₂.0.5C₄H₄O₄: 65.28% C; 6.40% H; 9.52%N; Found: 65.08% C; 6.35% H; 9.45N

EXAMPLE 531-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]propanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15.2mmol), K₂CO₃ (3 g) 1-[4-(3-bromopropoxy)-3-methoxyphenyl]propanone (4.6g, 18.2 mmol) in acetonitrile (100 ml) was heated at reflux for 2 hours.At the end of the reaction, the mixture was filtered and the solvent wasconcentrated and the residue was extracted into dichloromethane (300ml). The dichloromethane was filtered and concentrated again. The crudematerial (6.4 g) was purified by flash chromatography over a silica gelcolumn (SiO₂, 50 g; eluted with dichloromethane, 700 ml; 1% methanol indichloromethane, 1.4 l). The material thus purified (weight: 2.87 g,51%) was recrystallized from ethanol (25 ml) to give 2.13 g of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]propanoneas beige colored crystals, m.p.=118°-119° C.

ANALYSIS: Calculated for C₂₅H₂₉FN₂O₄: 68.16% C; 6.64% H; 6.36% N; Found:68.32% C; 6.63% H; 6.29N

EXAMPLE 544-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10.0mmol), K₂CO₃ (2.0 g) and 4-(3-bromopropoxy)-3-methoxybenzamide (2.32 g,8.0 mmol) in acetonitrile (80 ml) was heated at reflux for 5 hours. Atthe end of the reaction the solvent was evaporated. The residue wasextracted into dichloromethane. The inorganic insolubles were filteredoff. The dichloromethane was concentrated again. The crude residue waspurified by flash chromatography over a silica gel column (55 g, SiO₂;eluted with 1% methanol in dichloromethane, 1 l; 2% methanol indichloromethane, 1 l). The material thus obtained weighed 2.93 g (84%)as white crystals. Recrystallization from hot ethanol (60 ml) gave 2.2 gof4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamideas white crystals, m.p.=163°-164° C.

ANALYSIS: Calculated for C₂₃H₂₆FN₃O₄: 64.62% C; 6.13% H; 9.83% N; Found:64.20% C; 6.06% H; 9.71N

EXAMPLE 551-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylamino)-phenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.3 g, 10.3mmol), K₂CO₃ (1.4 g, 10.3 mmol),1-[4-(3-chloropropoxy)-3-(methylamino)phenyl]ethanone (2.5 g, 10.3mmol), KI (0.10 g), and acetonitrile (100 ml) was stirred at refluxunder nitrogen for 23 hours. The reaction was cooled to ambienttemperature, poured into water, and the aqueous mixture was extractedwith ethyl acetate. The ethyl acetate extract was washed twice withwater, dried with MgSO₄ and was concentrated to yield 4.8 g of a damp,brown solid. The compound was isolated by preparative HPLC (WatersAssociates prep LC/System 500, utilizing 2 silica gel columns and 4%methanol-methylene chloride as eluent). Concentration of appropriatefractions afforded 2.4 g. Recrystallization from ethanol gave 2.1 g of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylamino)phenyl]ethanoneas a beige solid, m.p.=151°-153° C.

ANALYSIS: Calculated for C₂₄H₂₈FN₃O₃: 67.75% C; 6.63% H; 9.88% N; Found:67.83% C; 6.76% H; 9.90N

EXAMPLE 561-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-ethoxyphenyl]-ethanone

A suspension of NaH (0.28 g of a 50% oil dispersion, 5.9 mmol) indimethylformamide (20 ml) was cooled to 4° C. in an ice bath. To thiswas added, dropwise,1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone(2.3 g, 0.0056 mol) dissolved in dimethylformamide (40 ml). After totaladdition, the mixture was stirred under nitrogen for 1 hour, keeping thetemperature below 10° C. A solution of bromoethane (1.3 g, 11.8 mmol)dissolved in dimethylformamide (15 ml) was then added, dropwise, to thereaction mixture. Stirring under nitrogen was continued for 3 hoursallowing the temperature to slowly rise to ambient temperature. Thereaction was cooled in an ice bath, water was added and the aqueousmixture was extracted with ethyl acetate. The ethyl acetate extract waswashed with water, dried with MgSO₄ and was concentrated to yield 3.9 gof a damp, beige solid. The solid was triturated with diethyl ether andfiltered to yield 1.5 g. This was combined with an additional sample(3.5 g total), and recrystallization from ethanol provided 3.0 g (57%)of glistening, beige crystals of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-ethoxyphenyl]ethanone,m.p.=112°-114° C.

ANALYSIS: Calculated for C₂₅H₂₉FN₂O: 68.16% C; 6.64% H; 6.36% N; Found:68.10% C; 7.03% H; 6.35N

EXAMPLE 57 1-[4-(3-Bromopropoxy)-3-(methylmercapto)-phenyl]ethanone

A mixture of 1-[4-hydroxy-3-(methylmercapto)phenyl]ethanone (5.4 g; 30mmol), K₂CO₃ (4.2 g), 1,3-dibromopropane (8 g, 39 mmol) in acetonitrile(150 ml) was heated at reflux for 3 hours and stirred at roomtemperature overnight. Acetonitrile was removed at reduced pressure andthe residue was extracted into dichloromethane (250 ml). Insolubles werefiltered off. The dichloromethane solution was concentrated. The crudeproduct was purified on a silica gel column (SiO₂, 100 g; eluted with3:2 hexane:dichloromethane, 1.6 l). The compound crystallized uponconcentration, and the product (3.5 g, 39%) was recrystallized fromethanol (40 ml) to yield1-[4-(3-bromopropoxy)-3-(methylmercapto)phenyl]ethanone as whiteneedles, 2.0 g; m.p.=120°-122° C.

ANALYSIS: Calculated for C₁₂H₁₅BrO₂S: 47.53% C; 4.99% H; Found: 47.74%C; 4.91% H

EXAMPLE 58 4-(3-Bromopropoxy)-3-methoxybenzonitrile

A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmol), K₂CO₃(12.5 g), and 1,3-dibromopropane (15 g, 75 mmol) in acetonitrile (100ml) was heated at reflux for 3 hours and left standing at roomtemperature overnight. The solvent of the reaction was removed on arotary evaporator, and the crude solid was extracted into methylenechloride (500 ml). The insolubles were filtered off. The dichloromethanesolution was concentrated and the material was purified on a flashchromatography column (SiO₂, 105 g; eluted with 2:3dichloromethane:hexane, and then with dichloromethane). The desiredproduct thus purified weighed 7.74 g (52%). Recrystallization twice fromethanol gave analytically pure 4-(3-bromopropoxy)-3-methoxybenzonitrile,m.p.=99°-101° C.

ANALYSIS: Calculated for C₁₁H₁₂BrNO₂: 48.91% C; 4.48% H; 5.19% N; Found:49.49% C; 4.47% H; 5.21N

EXAMPLE 59 1-[4-(3-Bromopropoxy)-3-methylphenyl]ethanone

A mixture of 4-hydroxy-3-methylacetophenone (14.5 g, 96 mmol), K₂CO₃(17.5 g, 144 mmol), and 1,3-dibromopropane (30 g, 144 mmol) inacetonitrile (400 ml) was heated at reflux for 6 hours. At the end ofthe reaction, the solvent was removed on a rotary evaporator, and thecrude solid was extracted into dichloromethane (750 ml). The insolubleinorganics were filtered off. The dichloromethane solution wasconcentrated again to a crude oil (34.5 g). Purification was effected byflash chromatography over a silica gel column (SiO₂, 150 g; eluted with7:3 hexane:dichloromethane, 2 1; and dichloromethane 2 l). The materialthus purified weighed 14.6 g (56%) and was recrystallized from ethanol.Recrystallization again from ethanol gave analytically pure1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone, m.p.=59°-61° C.

ANALYSIS: Calculated for C₁₂H₁₅BrO₂: 53.15% C; 5.58% H; Found: 53.35% C;5.52% H

EXAMPLE 60 1-[4-(3-Bromopropoxy)-3-methoxyphenyl]phenylmethanone

A mixture of 1-(4-hydroxy-3-methoxyphenyl)phenyl-methanone (14 g, 61.4mmol), K₂CO₃ (13 g, 92.1 mmol), and 1,3-dibromopropane (28 g, 86 mmol)in acetonitrile (400 ml) was heated at reflux for 4 hours. The reactionwas followed by thin layer chromatography. At the end of the reaction,the inorganics were filtered off and the solvent was removed on a rotaryevaporator. The residue was purified on a flash chromatography column(SiO₂, 140 g, eluted with 4:1 hexane:dichloromethane, 1.2 1) to give apartially solidifed material: 15.44 g (72%). Recrystallization twicefrom ethanol gave 2.84 g of1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone as white crystals,m.p.=88°-89° C.

ANALYSIS: Calculated for C₁₇H₁₇BrO₃: 58.47% C; 4.91% H; Found: 59.03% C;4.87% H

EXAMPLE 61N-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide(A) N-[2-(3-phenylsulfonyloxypropoxy)phenyl]acetamide

To a solution of N-[2-(3-hydroxypropoxy)phenyl]-acetamide (Example 113)(7.5 g, 36 mmol) in pyridine (90 ml), cooled to 0° C., was addedp-toluenesulfonyl chloride (13.6 g, 56 mmol). After the tosyl chloridewent into solution, the reaction was then allowed to stand at 5° C. for16 hours. The reaction was poured onto ice, and a brown oil settled. Theaqueous supernatant was decanted from the oil, and the residual oiltaken up in diethyl ether. The diethyl ether was washed with cold (5°C.) 3N HCl and then with brine. The organic layer was dried (MgSO₄), andconcentrated to afford a thick, brown oil, 5.3 g.

(B)N-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.4 g, 16mmol), N-[2-(3-phenylsulfonyloxypropoxy)phenyl]acetamide (5.3 g, 16mmol), K₂CO₃ (2.2 g), and acetonitrile (50 ml) was stirred and refluxedfor 5 hours. The reaction was poured into water, and the aqueoussuspension was extracted with ethyl acetate. The ethyl acetate waswashed (water and brine), dried (MgSO₄) and the solvent was concentratedto afford 6.0 g of a thick, brown oil. The oil was chromatographed on aWaters Prep 500 LC on silica gel. Concentration of the appropriatefractions afforded 3.0 g of a beige solid. This was recrystallized fromethyl acetate to yield (with concentration of the mother liquors) 2.2 g(33%) ofN-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamideas a beige solid, m.p.=118°-120° C.

ANALYSIS: Calculated for C₂₃H₂₆FN₃O₃: 67.14% C; 6.37% H; 10.21% N;Found: 67.06% C; 6.43% H; 10.23% N

EXAMPLE 621-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-dimethyl-aminophenyl]ethanone(A) 1-[4-(3-Chloropropory)-3-dimethylaminophenyl]ethanone

To a suspension of sodium hydride (2.3 g, 48.5 mmol of 50% oildispersion) with dimethylformamide (75 ml), and cooled to 3° C. in anice-salt bath and under a stream of nitrogen was added, dropwise,1-(4-hydroxy-3-dimethylaminophenyl)ethanone (8.7 g, 48.5 mmol) dissolvedin dimethylformamide (150 ml) so that the temperature did not go over 7°C. After the addition was over, the bath was removed and the reactionwas stirred at ambient temperature for 45 minutes. The ice bath wasreapplied and a solution of 1-bromo-3-chloropropane (8.4 g, 53.4 mmol)in dimethylformamide (25 ml) was added dropwise. After the addition wascomplete, the reaction was stirred for 18 hours at ambient temperatureunder nitrogen. The reaction was chilled to 7° C. in an ice bath andwater (200 ml) was carefully added. After stirring for 5 minutes, theaqueous mixture was extracted with ethyl acetate (5×200 ml). The ethylacetate extract was washed with water (2×50 ml), dried with MgSO₄, andconcentrated to yield 22.2 g of a black oily liquid. The compound waspurified by prep HPLC, and combination of appropriate fractions gave 5.0g of brown oil.

(B)1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-dimethylaminophenyl]ethanone

A mixture of 1-[4-(3-chloropropoxy)-3-dimethylaminophenyl]ethanone (2.9g, 11.3 mmol), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.3mmol), K₂CO₃ (1.7 g, 12.2 mmol), KI (200 mg) and acetonitrile (125 ml)was stirred at reflux for 18 hours. The cooled reaction was poured intowater and the aqueous mixture was extracted with ethyl acetate. Theethyl acetate extract was washed with water, dried with magnesiumsulfate and concentrated to yield 5.3 g of an amber oil. The compoundwas purified by preparative HPLC (Waters Associates prep LC/System 500utilizing 2 silica gel columns) and concentration of appropriatefractions provided 1.65 g (33%). After combining with two additionalsamples, the compound (3.4 g, 7.74 mmol total) was taken up in ethylacetate and fumaric acid (0.90 g, 7.75 mmol) was added. The mixture wasstirred at a mild reflux for 30 minutes and then for 1 hour at ambienttemperature. The reaction was left to stand overnight and was thenfiltered to give 3.6 g. The compound was recrystallized twice fromethanol to provide 2.3 g and once from acetonitrile to yield 1.9 g ofthe compound as a fumarate salt. The compound was converted to the freebase by suspending it in dilute NaOH and extracting withdichloromethane. After washing the dichloromethane extract with waterand drying with MgSO₄, the solvent was removed in vacuo to give 1.4 g(14%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-dimethylaminophenyl]ethanoneas a beige solid, m.p.=94°-96° C.

ANALYSIS: Calculated for C₂₅H₃₀FN₃O₃: 68.32% C; 6.88% H; 9.56% N; Found:67.74% C; 6.74% H; 9.40% N

EXAMPLE 631-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methoxyphenyl]ethanonehydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.4 g, 20mmol), 1-[4-(3-chloropropoxy)-2-methoxyphenyl]ethanone (4.8 g, 20 mmol),K₂CO₃ (2.8 g), KI (200 mg) and acetonitrile (110 ml) was stirred andrefluxed for 16 hours. The reaction was filtered and the filtrateconcentrated to afford 9.0 g of a brown oil. The oil was taken up inacetone and fumaric acid (2.5 g, 22 mmol) was added. The mixture washeated to reflux and then it was stirred at ambient temperature for 1hour. The resultant fumarate salt (7.0 g) was collected and thenreversed to the free base with aqueous sodium hydroxide to afford 4.6 gof a soft solid. The solid was flash chromatographed on silica gel withdichloromethane-methanol (10%) as eluent, and after concentration of theappropriate fractions afforded 3.6 g of an off-white solid. The solidwas dissolved in anhydrous ether and ethereal HCl was added toprecipitate 3.3 g of the hydrochloride salt. The salt was recrystallizedfrom ethanol to afford 3.3 g of product. Occluded alcohol was removed toyield 2.8 g (29%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methoxyphenyl]ethanonehydrochloride, m.p.=193°-195° C.

ANALYSIS: Calculated for C₂₄H₂₈ClFN₂O₄: 62.27% C; 6.10% H; 6.05% N;Found: 61.88% C; 5.90% H; 5.96% N

EXAMPLE 641-[4-(3-Chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone (A)4-(3-Chloropropoxy)-3-methoxybenzoic acid

To a stirred suspension under nitrogen of sodium hydride (6.4 g, 130mmol, of about 50% oil dispersion-ether washed) in tetrahydrofuran (220ml) was added pyrazole (4.4 g, 60 mmol) in tetrahydrofuran (60 ml),dropwise. After complete addition, the reaction was stirred for about 15minutes, and then 4-(3-chloropropoxy)-3-methoxybenzaldehyde (24.5 g, 107mmol) was added. The nitrogen was stopped and air was sparged into thereactor for about 3 hours. The reaction was then allowed to stir atambient temperature open to the atmosphere for 6 hours. Water was added,the reaction was cooled in an ice bath, and concentrated hydrochloricacid (25 ml) was added dropwise. More water was added and the yellowsolid that separated was collected to afford 16.2 g of product. Thefiltrate was then extracted with ethyl acetate to afford an additional9.3 g. The samples were combined and recrystallized from acetonitrile toyield 12.6 of a light, yellow solid, m.p.=154°-156° C. A 4.0 g samplewas recrystallized from acetonitrile to yield 2.6 g of a yellow solid.This combined with 0.4 g from another sample and recrystallized againfrom acetonitrile with charcoal treatment to afford 2.0 g of4-(3-chloropropoxy)-4-methoxybenzoic acid as a yellow solid,m.p.=157°-159° C.

ANALYSIS: Calculated for C₁₁H₁₃ClO₄: 54.00% C; 5.35% H; Found: 54.65% C;5.34% H

(B) 4-(3-Chloropropoxy)-3-methoxybenzoyl chloride

To a mixture of 4-(3-chloropropoxy)-3-methoxybenzoic acid (2.4 g, 10mmol) in dichloromethane (5 ml) was added thionyl chloride (0.9 ml, 12mmol) dissolved in dichloromethane (5 ml). The reaction was stirred andrefluxed for 1 hour, and then the dichloromethane was removed in vacuoto leave a dark oil. The oil was triturated with hexane and the solidthat formed while scratching with a glass rod was collected to afford1.6 g of 4-(3-chloropropoxy)-3-methoxybenzoyl chloride, m.p.=60°-63° C.

(C) 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone

To a stirred mixture of 4-(3-chloropropoxy)-3-methoxybenzoyl chloride(10.0 g, 38 mmol) in methylene chloride (55 ml) cooled to −70° C., therewas condensed into a reactor bromotrifluoromethane (70 g, 47 mmol).There was then added to the reactor hexamethylphosphoroustriamide (9.4g, 41 mmol) dissolved in dichloromethane (7 ml). The first 90% was addedquite rapidly, and the remainder at a slower rate. After completeaddition, the reaction was stirred at −70° C. to −65° C. for anadditional hour. The reaction mixture was allowed to come to roomtemperature. An equal volume of hexane was added and the layers wereseparated. The lower layer was extracted with hexane and then withdiethylether. The extracts were combined and concentrated to yield 5.6 gof a thick, colorless oil. The oil was chromatographed on a Waters Prep500 LC utilizing two silica gel columns and eluting with 20% ethylacetate-hexane. Concentration of appropriate fractions gave 2.7 g of alight oil, which after evacuation at high vacuum solidified to a waxy,white solid (2.4 g) of1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone.

EXAMPLE 654-[3-4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanol (A) 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone

A mixture of 1-[4-(3-chloropropoxy)-3-methoxy-phenyl]ethanone (10.0 g,41.2 mmol) and concentrated H₂SO₄ (50 ml) was stirred at 65° C. for 23hours. The cooled reaction was poured into 250 g of ice and was stirredvigorously for 10 minutes. The aqueous mixture was extracted withdichloromethane (CH₂Cl₂) and the resultant dichloromethane extract waswashed well with 5% sodium hydroxide. The basic phases were combined andwashed with dichloromethane. The aqueous mixture was cooled in an icebath and concentrated hydrochloric acid was added until a precipitateformed. The product was isolated by filtration and dried to yield 3.1 gof a light brown solid. This was combined with an additional sample (5.0g total) and two consecutive recrystallizations from toluene provided3.4 g (22%) of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone as abeige solid, m.p.=101°-103° C.

ANALYSIS: Calculated for C₁₁H₁₃ClO₃: 57.78% C; 5.73% H; Found: 58.17% C;5.66% H

(B) 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzene methanol

To a flask charged with sodium borohydride (1.5 g, 39.4 mmol) undernitrogen and chilled to 10° C. was added, slowly, a solution of1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (6.0 g, 26.2 mmol)dissolved in ethanol-tetrahydrofuran (120 ml, 2:1). After totaladdition, the ice bath was removed and the reaction was stirred atambient temperature for 3 hours. An additional amount of sodiumborohydride (0.2 g, 5.3 mmol) was carefully added. After stirring atambient temperature for one hour, the solvent was removed in vacuo. Theresultant solid residue was diluted with water (100 ml) and leftovernight. The product was isolated by vacuum filtration yielding 3.8 g.Two consecutive recrystallizations from toluene provided 3.3 g (55%) of4-(3-chloropropoxy)-3-hydroxy-α-methylbenzene methanol as a light brownsolid, m.p.=107°-109° C.

ANALYSIS: Calculated for C₁₁H₁₅ClO₃: 57.27% C; 6.55% H; Found: 57.60% C;6.43% H

(C)4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanol

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.3 g, 19.5mmol), 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzenemethanol (4.5 g,19.5 mmol), KI (200 mg), NaHCO₃ (1.8 g, 21.5 mmol) and CH₃CN (125 ml)was stirred at reflux under nitrogen for 24 hours. The cooled reactionwas filtered and the filter cake was washed with CH₃CN. The filtrate wasconcentrated to afford an oily residue, which was partitioned betweenwater and ethyl acetate. The ethyl acetate extract was washed withwater, dried with MgSO₄, and concentrated to yield 8.6 g of a dark oil.The oil was purified by preparative HPLC (Waters Associates prepLC/system 500) to yield 5.0 g. The compound was recrystallized twicefrom ethanol to provide 3.9 g (49%) of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-hydroxy-α-methyl-benzenemethanol as a light beige solid, m.p.=142°-144° C.

ANALYSIS: Calculated for C₂₃H₂₇FN₂O₄: 66.65% C; 6.57% H; 6.76% N; Found:66.68% C; 6.35% H; 6.72% N

EXAMPLE 662-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]anilinedihydrochloride (A) 2-(3-chloropropoxy)aniline

To a stirred suspension of sodium hydride (11.0 g, 230 mmol of a 50% oildispersion) in dimethylformamide (250 ml), under nitrogen, was added,dropwise, 2-aminophenol (25.0 g, 230 mmol) dissolved indimethylformamide (125 ml). After complete addition, the reaction wasstirred at ambient temperature for 1 hour, and then it was cooled to 5°C. (ice bath). 3-Chloro-1-bromopropane (36.2 g, 230 mmol) indimethylformamide (50 ml) was added, dropwise, so that the temperaturedid not go above 8° C. The reaction, was stirred for 4 hours and thenpermitted to stand at ambient temperature for 16 hours. The reaction waspoured into water and extracted with ethyl acetate. The ethyl acetatewas washed (water), dried (MgSO₄), and the solvent concentrated toafford 25.4 g of a reddish, dark oil. About 12.0 g of the oil waschromatographed on HPLC columns. Concentration of the largest fractionsgave 5.4 g of 2-(3-chloropropoxy)aniline as an oil.

(B)2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]anilinedihydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.8 g, 22mmol), 2-(3-chloropropoxy)aniline (4.0 g, 22 mmol), K₂CO₃ (4.1 g, 22mmol), KI (0.2 g), and acetonitrile (100 ml) was stirred and refluxedfor 10 hours. The reaction was poured into water and the aqueous mixturewas extracted with ethyl acetate. The extract was washed (water), dried(MgSO₄), and the solvent was concentrated to afford 9.0 g of a redsolid. The solid was triturated with diethyl ether to yield 3.0 g of abeige solid. This sample was combined with a sample (1.1 g) from anotherrun, and a hydrochloride salt was prepared by dissolving the free basein ethanol and then adding ethereal HCl. The resultant salt (3.5 g) wasrecrystallized twice from methanol-diethyl ether to afford 2.6 g (22%)of2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]anilinedihydrochloride as a brown solid, m.p.=253°-255° C.

ANALYSIS: Calculated for C₂₁H₂₄FN₃O₂2HCl: 57.02% C; 5.92% H; 9.50% N;Found: 56.68% C; 5.71% H; 9.35% N

EXAMPLE 67N-[5-Acetyl-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]-acetamide(A) Preparation of 1-[3-acetylamino-4-(3-chloropropoxy)phenyl]ethanone

A stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl]ethanone (7.7 g,40 mmol), K₂CO₃ (5.7 g), 3-chloro-1-bromopropane (8.9 g, 56 mmol) andacetone (100 ml) was refluxed for 16 hours. The reaction was allowed tocool to ambient temperature and filtered. Concentration of the filtrateyielded 8.5 g of a white solid. The solid was recrystallized fromtoluene and then from ethanol to afford 6.5 g of an off-white solid. A3.3 g sample of this material was flash chromatographed on silica gelwith ethyl acetate as eluent. Concentration of the appropriate fractionsafforded 2.8 g of a solid. The solid was recrystallized from toluene andthen from ethanol-water to yield 2.2 g (51%) of a solid, m.p.=124°-126°C.

ANALYSIS: Calculated for C₁₃H₁₆ClNO₃: 57.89% C; 5.98% H; 5.19% N; Found:57.08% C; 5.85% H; 5.13% N

(B)N-[5-acetyl-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.4 g, 20mmol), 1-[3-acetylamino-4-(3-chloropropoxy)phenyl]ethanone (5.5 g, 20.5mmol), K₂CO₃ (2.8 g), and acetonitrile (70 ml) was stirred and refluxedfor 16 hours. The reaction was poured into water and the aqueous mixturewas extracted with ethyl acetate. The extract was washed (water), dried(MgSO₄), and then it was concentrated to afford 9.5 g of a brown oil.The oil was taken up in ethyl acetate and ethereal HCl was added untilthe reaction was acidic. The crude, brown, hydrochloride salt wascollected (8.4 g), and was immediately converted to the free base withNH₄OH, to afford 5.4 g of the compound as a brown oil. The oil waschromatographed on a Waters Preparative HPLC utilizing silica gelcolumns. Concentration of the appropriate fractions yielded 3.5 g ofN-[5-acetyl-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-phenyl]acetamideas a white solid, m.p.=108°-110° C.

ANALYSIS: Calculated for C₂₅H₂₈FN₃O₄: 66.21% C; 6.22% H; 9.27% N; Found:66.12% C; 6.25% H; 9.27% N

EXAMPLE 683-[1-[3-(4-Ethyl-3-methoxyphenoxy)propyl]-4-piperidinyl-6-fluoro-1,2-benzisoxazolehydrochloride (A) 4-ethyl-2-methoxyphenol

Acetovanillone (Aldrich, 11.0 g, 66 mmol) was dissolved in absoluteethanol (200 ml) and added to 1.5 g of 5% palladium on carbon. A fewdrops of concentrated hydrochloric acid were added and the mixturehydrogenated on a shaker at 42 psi. The reaction mixture was filteredthrough Celite, and the filtrate was concentrated to afford 10.3 g of agolden liquid. This was diluted with water, extracted with diethyl etherand the organic phase was washed with water and sodium bicarbonate. Thesolvent was dried (MgSO₄) and concentrated to afford 9.3 g of a slightlyyellow liquid.

(B) 4-ethyl-2-methoxy-4-(3-chloropropoxy)benzene

A mixture of 4-ethyl-2-methoxyphenol (9.0 g, 59 mmol),3-chloro-1-bromopropane (13.0 g, 83 mmol), K₂CO₃ (6.2 g) and acetone(200 ml) was stirred and refluxed for 16 hours. The reaction was allowedto cool, and then it was filtered. The filtrate was concentrated to aclear liquid. The liquid was diluted with dilute aqueous NaOH, and thebasic mixture was extracted with diethyl ether. The diethyl ether waswashed (water), dried (MgSO₄), and the solvent was concentrated toafford 11.9 g of a golden liquid. The liquid was flash chromatographed.This gave a colorless liquid, 9.9 g of4-ethyl-2-methoxy-4-(3-chloropropoxy)benzene.

(C)3-[1-[3-(4-ethyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.0g, 18 mmol), KI (0.4 g), K₂CO₃ (2.5 g),4-ethyl-2-methoxy-4-(3-chloropropoxy)benzene (4.4 g, 18 mmol) andacetonitrile was refluxed for 8 hours. The reaction was poured intowater, and the aqueous suspension was extracted with ethyl acetate. Theethyl acetate extract was washed (water) dried (MgSO₄) and the solventconcentrated to afford 7.0 g of a brown oil. The oil was combined with2.0 g from another sample, and the combined sample was flashchromatographed on silica gel. Concentration of the appropriatefractions yielded 4.4 g of a thick oil, which solidified on standing.The solid was dissolved in ethyl acetate and ethereal HCl was added toprecipitate 4.5 g of a white hydrochloride salt. Recrystallization fromacetone afforded 3.0 g (29%) of3-[1-[3-(4-ethyl-2-methoxyphenoxy)-propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride as a white solid, m.p.: 150°-152° C.

ANALYSIS: Calculated for C₂₄H₂₉FN₂O₃.HCl: 64.21% C; 6.74% H; 6.24% N;Found: 64.38% C; 6.84% H; 6.14% N

EXAMPLE 691-[3,5-Dimethoxy-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-phenyl]-ethanone(A) 3,5-dimethoxy-4-(3-bromopropoxy)acetophenone

To 3,5-dimethoxy-4-hydroxyacetophenone (5.2 g) in dimethylformamide (50ml) at 0° C. under nitrogen, was added sodium hydride (700 mg, 1.1 eq.98%). The resulting mixture was stirred for ten minutes until evolutionof gas ceased. Potassium carbonate (4 g) was added, and then1,3-dibromopropane was added. The mixture was heated at 60° C. for onehour. When the reaction was complete, the mixture was poured into awater/ice mixture and the resulting solution was extracted with ethylacetate (600 ml). The ethyl acetate was washed with water, brine, andthen concentrated to an oil (9 g). The product was purified bychromatography on silica gel to yield3,5-dimethoxy-4-(3-bromopropoxy)acetophenone as a light oil, 7.6 g.

(B)1-[3,5-dimethoxy-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-phenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0g, 3.6 mmol), K₂CO₃ (2.1 g, 15 mmol), and3,5-dimethoxy-4-(3-bromopropoxy)acetophenone (4.4 g, 13.8 mmol) inacetonitrile (50 ml) was heated at reflux for 3 hours. At the end of thereaction, the mixture was diluted with dichloromethane 200 ml). Theinsolubles were filtered. The solution was concentrated to an oil (10g). The purification was done by flash chromatography on a silica gelcolumn. The product was obtained as a colorless oil (3.85 g, 61%), whichcrystallized from ethanol (400 ml) to give 2.94 g of1-[3,5-dimethoxy-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]phenyl]ethanoneas off-white crystals, m.p.=107°-108° C.

ANALYSIS: Calculated for C₂₅H₂₉FN₂O₅: 65.78% C; 6.40% H; 6.14% N; Found:65.84% C; 6.44% H; 6.15% N

EXAMPLE 70N-[3-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamidehemifumarate (A) 3-(3-acetamidophenoxy)propyl bromide

To 3-acetamidophenol (15.1 g) in dichloromethane (500 ml, dry) was addedpotassium carbonate (20 g) and then 1,3-dibromopropane (30 g). Theresulting mixture was heated at reflux for 6 hours and then overnight atroom temperature. After an additional 24 hours, the reaction wascomplete. Solids were filtered from the reaction mixture, and thesolution was concentrated to an oil, which was purified to yield3-(3-acetamidophenoxy)propyl bromide, 13.2 g.

(B)N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamidehemifumarate

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.25g, 42 mmol), K₂CO₃ (8 g, 58 mmol) and 3-(3-acetamidophenoxy)propylbromide (11.4 g, 42 mmol) in acetonitrile (350 ml) was heated at refluxfor 3 hours. At the end of the reaction, the reaction was cooled,filtered and the solids washed with dichloromethane (100 ml). Theorganic solvent was removed on a rotary evaporator to leave a crude oil(18 g). Purification was by flash chromatography on a silica gel column.The product thus purified was an oil, 12.2 g, 70%. Analytically puresample was prepared by dissolving 3 g of free base in ethanol andtreating with fumaric acid solution in ethanol (850 mg:5 ml). TheN-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]phenyl]acetamidehemifumarate crystals obtained weighed 2.73 g, m.p.=184°-186° C.

ANALYSIS: Calculated for C₂₃H₂₆FN₃O₂.0.5C₄H₄O₄: 63.95% C; 6.01% H; 8.94%N; Found: 63.47% C; 5.94% H; 8.78% N

EXAMPLE 713-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]aniline

A stirred mixture ofN-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide(9.2 g, 22 mmol), prepared as described in the previous example, in 15%hydrochloric acid (110 ml) was heated at 100° C. for 2.5 hours until ahomogeneous solution resulted. The reaction was cooled to 0° C. in anice bath and basified with 50% NaOH. The product was extracted withethyl acetate (3×200 ml). The ethyl acetate solution was washed withwater, brine, then dried over Na₂SO₄. The solvent was removed. The crudeproduct was purified on a flash chromatography column. The product thusobtained was a solid: 6.6 g (80%). Recrystallization from hot ethanol(50 ml) gave3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]anilineas off-white crystals; 3.46 g, m.p.=115°-117° C.

ANALYSIS: Calculated for C₂₁H₂₄FN₃O₂: 68.27% C; 6.55% H; 11.37% N;Found: 68.34% C; 6.53% H; 11.31% N

EXAMPLE 723-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyaniline

A mixture of3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenylacetamide(4.2 g, 9.5 mmol), prepared as in Example 26 above, in 15% hydrochloricacid (60 ml) was heated at reflux (110° C.) for 2 hours. At the end ofthe reaction, the solution was cooled to 0° C. then basified with 25%NaOH to pH of 10. The product was extracted into ethyl acetate (300 ml).The ethyl acetate solution was washed with water and brine, then driedover Na₂SO₄. The solvent was removed at reduced pressure. The crude oilwas purified by flash chromatography on a silica gel column. The productthus purified was an oil, 2.6 g. Crystallization from ethanol (5 ml) andpetroleum ether (3 ml) yielded3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-4-methoxyanilineas fine crystals: 1.2 g; m.p.=94°-95° C.

ANALYSIS: Calculated for C₂₂H₂₆FN₃O₃: 66.15% C; 6.56% H; 10.52% N;Found: 66.16% C; 6.54% H; 10.44% N

EXAMPLE 731-[4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy-3-methylamino-phenyl]ethanonefumarate (A) 1-[(3-N-acetyl-N-methylamino)-4-hydroxyphenyl]ethanone

A solution of 2-methoxy(methylamino)benzene (26.0 g, 190 mmol) and1,2-dichloroethane was cooled to 10°-15° C. and a solution of acetylchloride (33.8 g, 430 mmol) dissolved in dichloroethane (50 ml) wasdripped in slowly. Following this addition, an additional 100 mldichloroethane was added. The reaction was cooled to 0° C. and aluminumchloride (72.3 g, 540 mmol) was added over the course of 45 minutes sothat the temperature did not exceed 10° C. After complete addition, thereaction was heated to reflux and was stirred for 18 hours undernitrogen. The reaction was cooled and was poured into ice. The resultingaqueous phase was extracted further with dichloromethane and thecombined extracts were washed with H₂O, dried with MgSO₄, andconcentrated to yield 32.0 g of1-[(3-N-acetyl-N-methylamino)-4-hydroxyphenyl]ethanone as a brown solid,m.p.=168°-171° C.

(B) 1-(4-hydroxy-3-methylaminophenyl)ethanone

A mixture of 1-[(3-N-acetyl-N-methylamino)-4-hydroxyphenyl]ethanone(15.0 g, 72.4 mmol) and concentrated HCl (150 ml) was stirred at refluxfor 3 hours. The heat was terminated and the reaction stood overnight.The reaction mixture was transferred to a 1 L beaker and was chilled inan ice-salt bath. Solid sodium bicarbonate was added cautiously untilthe pH was about 2, and the aqueous mixture was allowed to standovernight. The reaction mixture was continued to be made basic by theaddition of solid sodium bicarbonate. After pH 8 was achieved, thereaction mixture was extracted with ethyl acetate. The ethyl acetateextract was washed with a 200 ml aliquot of water and this was then fedthrough a bed of Celite. After washing the cake with fresh ethyl acetatethe phases were separated. The ethyl acetate extract was washed severalmore times with water, dried with MgSO₄ and concentrated to yield 10.5 gof a dark solid of 1-(4-hydroxy-3-methylaminophenyl)ethanone.

(C) 1-[4-(3-chloropropoxy)-3-methylaminophenyl]ethanone

To a stirred suspension of sodium hydride (0.87 g, 18.2 mmol of a 50%oil dispersion) in dimethylformamide (25 ml) under nitrogen and cooledto 0° in an ice-salt bath was added, dropwise, a solution of1-(4-hydroxy-3-methylamino-phenyl)ethanone (3.0 g, 18.2 mmol) dissolvedin dimethylformamide (55 ml) so that the temperature did not rise above3° C. After the addition was complete, the reaction was stirred for 80minutes at ambient temperature. The reaction was cooled to 5° C. and asolution of 1-bromo-3-chloropropane (3.1 g, 0.0120 mol) indimethylformamide (20 ml) was added dropwise. After this addition wascomplete, the ice bath was removed and the reaction was stirred atambient temperature for 2.5 hours. Water (75 ml) was carefully added andafter stirring vigorously for 5 minutes, the reaction was left to standovernight. The aqueous mixture was extracted with ethyl acetate and theethyl acetate extract was washed with water, dried with MgSO₄, andconcentrated to yield 3.9 g of a dark solid. The compound was purifiedby preparative HPLC to afford 2.4 g of a beige solid. This was combinedwith an additional sample (3.8 g total) and two consecutiverecrystallizations from ethanol gave 2.1 g (31%) of1-[4-(3-chloropropoxy)-3-methyl-aminophenyl]ethanone as a fluffy, beigesolid, m.p.=115°-117° C.

ANALYSIS: Calculated for C₁₂H₁₆ClNO₂: 59.63% C; 6.67% H; 5.79% N; Found:59.49% C; 6.64% H; 5.79% N

(D)1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy-3-methylaminophenyl]ethanonefumarate

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (1.9g, 79 mmol), 1-[4-(3-chloropropoxy)-3-methylaminophenyl]ethanone (1.9 g,79 mmol), K₂CO₃ (1.1 g), KI (0.1 g), and acetonitrile (95 ml) wasrefluxed for 16 hours. The reaction was poured into water and theaqueous suspension extracted with ethyl acetate. The extract was washed(water and brine), dried (MgSO₄), and then the solvent was concentratedto afford 3.2 g of a thick, brown oil. The oil was chromatographed on aWaters Prep 500 LC on silica gel columns, and concentration of theappropriate fractions afforded 1.5 g of a brown oil. The oil wasdissolved in acetone and fumaric acid (0.4 g, 0.003 mol) was added, and1.9 g of a white fumarate salt was collected. The salt wasrecrystallized from dimethylformamide to yield 1.1 g (25%) of1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy-3-methylaminophenyl]ethanonefumarate as a white solid, m.p.=198°-200° C.

ANALYSIS: Calculated for C₂₈H₃₂FN₃O₆S: 60.31% C; 5.78% H; 7.54% N;Found: 60.02% C; 5.88% H; 7.68% N

EXAMPLE 74N-[3-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-4-methoxy-phenyl]acetamide(A) N-[3-(3-chloropropoxy)-4-methoxyphenyl]acetamide

To a stirred suspension, under nitrogen, of sodium hydride (1.8 g, 38mmol) in dimethylformamide (60 ml) was added dropwise,N-(3-hydroxy-4-methoxy)acetamide (6.1 g, 34 mmol) dissolved indimethylformamide (23 ml). After complete addition, the reaction wasstirred at ambient temperature for 0.5 hour, and then3-chloro-1-bromopropane (5.2 g, 33 mmol) in dimethylformamide (10 ml)was added, dropwise. The reaction was stirred at ambient temperature for16 hours, and then it was poured into water, and the aqueous mixture wasextracted with ethyl acetate. The extract was washed (water), dried(MgSO₄) and the solvent concentrated to afford a purple solid. The solidwas triturated with diethyl ether and collected to afford 2:8 g of apurple solid. This sample was combined with a sample (1.2 g) fromanother run and was recrystallized from toluene twice to yield 2.9 g ofan off-white solid. The solid was flash chromatographed on 200 g ofsilica gel, eluting the column with ethyl acetate, and subsequentconcentration of the appropriate fractions afforded 2.4 g of a whitesolid. Recrystallization of the compound from toluene yielded 2.2 g(17%) of N-[3-(3-chloropropoxy-4-methoxyphenyl]acetamide, m.p.=112°-114°C.

ANALYSIS: Calculated for C₁₂H₁₆ClNO₃: 55.93% C; 6.26% H; 5.44% N; Found:56.25% C; 6.29% H; 5.44% N

(B)N-[3-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]acetamide

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.0g, 17 mmol), N-[3-(3-chloropropoxy)-4-methoxyphenyl]acetamide (4.3 g, 17mmol), K₂CO₃ (2.3 g), KI (0.2 g) and acetonitrile (200 ml) was refluxedfor 10 hours. The cooled reaction mixture was filtered and the filtratewas concentrated to yield a dark oil. The oil was dissolved in acetone,and ethereal HCl was added to yield 5.7 g of a yellow hydrochloridesalt. The salt was reversed to the free base and the resultant oil (5.2g) was chromatographed on a Waters Associates Prep LC utilizing silicagel columns. Concentration of the appropriate fractions yielded 4.7 g ofan oil, which was converted to a hydrochloride salt. The salt wasconverted to its free base yielding 2.8 g of a brown oil. The oil wasstirred vigorously with ether to yield 1.4 g (18%) ofN-[3-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]-acetamideas a white solid, 1.4 g, m.p.=109°-111° C.

ANALYSIS: Calculated for C₂₄H₂₈FN₃O₃S: 63.00% C; 6.17% H; 9.18% N;Found: 62.80% C; 6.17% H; 8.86% N

EXAMPLE 75 1-[4-[344-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxy-phenyl]ethanonehydrochloride

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.0g, 17 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.1 g, 17mmol), K₂CO₃ (2.3 g), KI (0.2 g), and acetonitrile (100 ml) was refluxedfor 9 hours. The reaction was poured into water, and the aqueous mixturewas extracted with ethyl acetate. The extract was washed (water), dried(MgSO₄), and the solvent was concentrated to afford 8.0 g of a brownoil. The oil was chromatographed on a Waters Prep 500 HPLC on silica gelcolumns. Concentration of the appropriate fractions afforded a gum-likeresidue, which upon trituration with isopropyl ether afforded 1.9 g of awhite solid. The solid was dissolved in absolute ethanol, and etherealHCl was added to precipitate 1.7 g of a hydrochloride salt.Concentration of the isopropyl ether filtrate, and similar treatment ofthe residue, afforded an additional 0.5 g of the salt. The samples werecombined and recrystallized from absolute ethanol to yield 1.7 g (21%)of1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanonehydrochloride as a white solid, m.p.=221°-223° C.

ANALYSIS: Calculated for C₂₄H₂₇FN₂O₃S.HCl: 60.18% C; 5.89% H; 5.85% N;Found: 60.01% C; 5.97% H; 5.79% N

EXAMPLE 76N,N-Dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide(A) N,N-dimethyl-4-bromopropoxy-3-methoxybenzamide

To N,N-dimethyl-4-hydroxy-3-methoxybenzamide (5.64 g, 28.7 mmol) inacetonitrile (450 ml) was added potassium carbonate (7.9 g) followed by1,3-dibromopropane (11.6 g). The resulting reaction mixture was refluxedfor 3 hours and stirred at room temperature for 12 hours. The mixturewas filtered and concentrated to an oil. Following purification bycolumn chromatography, N,N-dimethyl-4-bromopropoxy-3-methoxybenzamide asa colorless oil (7.6 g) was obtained.

(B)N,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.9g, 17.7 mmol), N,N-dimethyl-4-bromopropoxy-3-methoxybenzamide (5.54 g,17.5 mmol) and K₂CO₃ (3 g) in acetonitrile (250 ml) was heated at refluxfor one hour. At the end of the reaction, the insolubles were filteredand washed with dichloromethane. The solvent was removed on a rotaryevaporator. The residue was purified by flash chromatography over asilica gel column. The product thus obtained as an oil weighed 7 g.Crystallization from hot ethanol (45 ml) afforded analytically pureN,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide,3.95 g, 50%, as light yellow crystals, m.p.=126°-127° C.

ANALYSIS: Calculated for C₂₅H₃₀FN₃O₄: 65.92% C; 6.64% H; 9.22% N; Found:65.76% C; 6.64% H; 9.14% N

EXAMPLE 771-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanoneoxime

A mixture of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone(4.3 g, 10 mmol), prepared as in Example 3 above, hydroxylaminehydrochloride (1.3 g, 18 mmol), ammonium acetate (1.7 g, 22 mmol) andethanol-H₂O was stirred and refluxed for 16 hours. The reaction waspoured into water, and the mixture was cooled in an ice bath for 2hours. The resultant, white solid was collected, washed with water anddried to yield 4.6 g of hydrochloride salt of the oxime, m.p.=216°-218°C. The compound was dispersed in water and ammonium hydroxide was addeduntil the suspension was decidedly basic. The basic suspension was thenextracted with dichloromethane, and after washing with water, drying(MgSO₄), and concentrating the extract, 3.0 g of white solid melting at168°-170° C. were harvested. The compound was recrystallized fromdimethylformamide to yield 2.3 g (52%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanoneoxime as a white solid, m.p.=168°-170° C.

ANALYSIS: Calculated for C₂₄H₂₈FN₃O₄: 65.29% C; 6.39% H; 9.52% N; Found:65.27% C; 6.44% H; 9.46% N

EXAMPLE 781-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]ethanoneoxime O-methyl ether

A solution of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]ethanone(4.3 g, 10 mmol), prepared as in Example 3 above, methoxylaminehydrochloride (0.9 g, 10 mmol) in pyridine (75 ml)/ethanol (75 ml) wasrefluxed for 16 hours. Most of the solvent was evaporated under reducedpressure, and the residue was diluted with water to precipitate 1.6 g ofa white solid, m.p. 200°-201° C. The aqueous filtrate upon standingdeposited another crop of white crystals, which yielded 1.2 g of a pale,yellow solid with a m.p. of 70°-72° C. The initial crop of crystals wasconverted to its free base with aqueous NaOH. After extractive workupwith ethyl acetate, 1.2 g of the free base was obtained. The two sampleswere combined and recrystallized from isopropyl ether to afford 2.0 g(44%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]ethanoneoxime O-methyl ether as colorless crystals, m.p.=97°-99° C.

ANALYSIS: Calculated for C₂₅H₃₀FN₃O₄: 65.92% C; 6.64% H; 9.22% N; Found:65.89% C; 6.86% H; 9.15% N

EXAMPLE 791-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanonehydrazone

A stirred mixture of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone(4.3 g, 10 mmol), prepared as in Example 3 above, hydrazine (0.8 g, 2.5mmol), and ethanol (40 ml) was refluxed for 16 hours. The cooledsolution was concentrated to yield an oily residue. The residue wastriturated with water and the resultant solid was collected to afford4.2 g of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanonehydrazone as a yellow solid. The compound was recrystallized fromisopropanol and then from toluene to afford 1.7 g (39%). m.p.=106°-108°C.

ANALYSIS: Calculated for C₂₄H₂₉FN₄O₃: 65.44% C; 6.64% H; 12.72% N;Found: 65.38% C; 6.55% H; 12.55% N

EXAMPLE 806-Fluoro-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehydrochloride

A solution of butyllithium (4.7 ml of a 2.3M solution in hexanes, 10.7mmol) in tetrahydrofuran (65 ml) was stirred under nitrogen and cooledto −70° C. in an isopropyl alcohol-dry ice bath.Methyltriphenylphosphonium bromide (3.8 g, 10.6 mmol) was addedportionwise over the course of 10 minutes. After complete addition, thereaction was stirred at −65° C. for one hour and was then allowed togradually warm up to ambient temperature, where it was stirred for anadditional 3.5 hours. The reaction was cooled to 0° C., and a solutionof1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanoneprepared as in Example 3 above (4.7 g, 0.0110 mol) dissolved intetrahydrofuran (50 ml) was added, dropwise, over the course of 30minutes. After the addition was complete, the reaction was stirred atambient temperature for 19 hours. The reaction was poured into water andthe aqueous mixture was extracted with diethyl ether. The diethyl etherextract was washed several times with water, dried with MgSO₄ andconcentrated to yield 7.0 g of a light orange solid. Recrystallizationfrom toluene-hexane provided 1.4 g of triphenylphosphine oxide andconcentration of the filtrate afforded 5.5 g of a glassy, beige solid.This was combined with an additional sample (6.5 g total) andpurification by preparative HPLC (Water's Associates prep LC/System 500)gave 5.2 g of beige solid, which remained contaminated bytriphenylphosphine oxide. The compound was taken up in anhydrous ethanol(300 ml) and methanol (5 drops) and ethereal HCl was added toprecipitate 4.0 g of a pale, white solid, m.p.=192°-194° C.

ANALYSIS: Calculated for C₂₅H₃₀ClFN₂O₃: 65.14% C; 6.56% H; 6.08% N;Found: 64.95% C; 6.62% H; 6.04% N

EXAMPLE 81(E)-1-[4-[[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxyphenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10mmol), K₂CO₃ (2 g), (E)-4-[(4-bromo-2-butenyl)oxy]-3-methoxyacetophenone(4.0 g, 1.3 eq) in acetonitrile (100 ml) was heated at reflux for 2hours. At the end of the reaction, the solvent was removed on the rotaryevaporator. The residue was extracted into dichloromethane (300 ml). Theinsolubles were filtered off. The dichloromethane was concentrated. Thecrude product was purified on a flash chromatography column. The producteluted as an oil, weight 2.87 g (64%). Recrystallization fromethanol:hexane (20 ml:5 ml) gave(E)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3methoxy-phenyl]ethanoneas off-white crystals: 2.46 g; m.p.=91°-93° C.

ANALYSIS: Calculated for C₂₅H₂₇FN₂O₄: 68.48% C; 6.21% ; 6.39% N; Found:68.28% C; 6.12% H; 6.27% N

EXAMPLE 82 (Z)-1-[4-[(4-Chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone

A stirred mixture of 4-hydroxy-3-methoxyacetophenone (16.6 g, 10 mmole),K₂CO₃ (14 g, 100 mmol) and cis-1,4-dichloro-2-butene (Aldrich, 15 g, 120mmol) in acetonitrile (250 ml) was heated at reflux for 2.5 hours. Themixture was filtered and concentrated to an oil. Purification was byflash chromatography. The fractions containing the purest product werecombined and concentrated to give white crystals, 7.7 g, 30%. This wasrecrystallized from ether to give analytical pure(Z)-1-[4[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone (2.72 g),m.p.=64°-66° C.

ANALYSIS: Calculated for C₁₃H₁₅ClO₃: 61.30% C; 5.94% H; Found: 61.28% C;5.94% H

EXAMPLE 83(Z)-1-[4-[[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxyphenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2g, 10 mmol), K₂CO₃ (1.8 g, 13 mmol) and(Z)-1-[4-[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone (3.43 g, 9.7mmol) in acetonitrile (100 ml) was heated at reflux for 1½ hours. At theend of the reaction, the solvent was removed and the inorganics werefiltered after addition of dichloromethane (250 ml). The dichloromethanesolvent was removed again. The crude oil was purified on two flashchromatography columns to give a colorless oil (2.78 g). The oil wassolidified by vigorously drying on a vacuum pump. Recrystallization fromethanol (10 ml) and hexane (2 ml) gave analytically pure(Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxyphenyl]ethanone,1.83 g, m.p.=57°-59° C.

ANALYSIS: Calculated for C₂₅H₂₇FN₂O₄: 68.48% C; 6.21% H; 6.39% N; Found:68.26% C; 6.18% H; 6.32% N

EXAMPLE 84(E)-1-[3-[[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxyl-4-hydroxyphenyl]ethanonehydrochloride

The mixture of(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanone(5.5 g, 10.7 mmol), acetic acid (50 ml), and hydrochloric acid (6 ml)was heated at 75° C. for 2 hours. At the end of reaction, the solventwas reduced to about 20 ml on a rotary evaporator. The solution waspoured into ice water (350 ml) and extracted with dichloromethane (3×250ml). The dichloromethane solution was washed with brine and dried overNa₂SO₄. A solid formed on concentration of the solvent. This wascollected by filtration (3.4 g). Recrystallization from hot methanol (40ml) gave 1.82 g of(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-hydroxyphenyl]ethanonehydrochloride as white crystals, 37.5%, m.p.=208°-210° C.

ANALYSIS: Calculated for C₂₄H₂₅FN₂O₄.HCl: 62.54% C; 5.69% H; 6.08% N;Found: 62.40% C; 5.60% H; 6.04% N

EXAMPLE 85(E)-1-[3-[[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanone(A) (E)-3-[(4′-bromo-2′-butenyl)oxy]-4-benzyloxyacetophenone

To 4-benzyloxy-3-hydroxyacetophenone (17.6 g) in acetonitrile (200 ml)was added potassium carbonate (10 g), followed by the addition of(E)-1,4-dibromobutene (19 g). The resulting mixture was heated at refluxfor 3 hours. The mixture was concentrated, extracted intodichloromethane, and the potassium salt was removed by filtration.Solvent was removed, and the resulting material was purified by flashchromatography to yield 20.5 g of(E)-3-[(4′-bromo-2′-butenyl)oxy]-4-benzyloxyacetophenone as whitecrystals.

(B)(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzoisoxazole (5.62 g, 25.5mmol), K₂CO₃ (4 g, 29 mmol), and(E)-3-[(4′-bromo-2′-butenyl)oxy]-4-benzyloxy-acetophenone (10 g, 26.6mmol) in acetonitrile (125 ml) was heated at reflux for 3.5 hours. Themixture was cooled and concentrated to a crude solid. The residue wasextracted into dichloromethane (300 ml) and insolubles were filtered.The crude material from the dichloromethane solution was purified on aflash chromatography column. The product thus purified weighed 8 g as apale white solid. Recrystallization from hot ethanol gave 7.11 g of(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanoneas off-white crystals, m.p.=124°-125° C.

ANALYSIS: Calculated for C₃₁H₃₁FN₂O₄: 72.36% C; 6.07% H; 5.44% N; Found:72.23% C; 6.04% H; 5.04% N

EXAMPLE 866-Fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole(A) 6-(3-Chloropropoxy)-5-methoxyindole

To a stirred suspension of sodium hydride (0.94 g, 19.6 mmol of a 50%oil dispersion) in dimethylformamide (20 ml) under nitrogen and cooledto −5° C. was added, dropwise, 5-methoxy-6-hydroxyindole (3.2 g, 19.6mmol) dissolved in dimethylformamide (60 ml) so that the temperature didnot exceed −2° C. After complete addition, the reaction was stirred for45 minutes at 0° C. While maintaining the reaction temperature between−5° C. and 0° C., a solution of 1-bromo-3-chloropropane (3.1 g, 19.6mmol) dissolved in dimethylformamide (15 ml) was slowly added. Themixture was stirred at ambient temperature under nitrogen for 21 hours.The reaction was cooled in an ice bath, and water was added to destroythe excess sodium hydride, and the aqueous mixture was extracted withethyl acetate. The ethyl acetate extract was washed with water, driedwith MgSO₄ and concentrated to yield 5.3 g of a dark, oily liquid. Thiswas combined with an additional sample, for a total of 10.0 g, andpurification by preparative HPLC (Waters Associates prep (LC/System 500)provided 5.1 g of a brown solid. A 2.5 g sample was recrystallized fromisopropyl alcohol to yield 1.1 g (30%) of6-(3-chloropropoxy)-5-methoxyindole as beige crystals, m.p.=73°-75° C.

ANALYSIS: Calculated for C₁₂H₁₄ClNO₂: 60.13% C; 5.89% H; 5.84% N; Found:60.26% C; 5.86% H; 5.77% N

(B)6-Fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.5mmol), 6-(3-chloropropoxy)-5-methoxyindole (2.5 g, 10.4 mmol), K₂SO₃(1.6g, 11.5 mmol), KI (200 mg) and acetonitrile (100 ml) was stirred atreflux under nitrogen for 40 hours. The cooled reaction was poured intowater and extracted with ethyl acetate. The ethyl acetate extract waswashed with water, washed with brine, dried with MgSO₄ and concentratedto yield 4.0 g of a solid. The compound was recrystallized from ethanolto afford 3.3 g. Another recrystallization from ethanol (utilizing acharcoal treatment) provided 2.9 g (66%) of6-fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]-propyl]-4-piperidinyl]-1,2-benzisoxazoleas a beige solid, m.p.=156°-158° C.

ANALYSIS: Calculated for C₂₄H₂₆FN₃O₃: 68.07% C; 6.19% H; 9.92% N; Found:67.89% C; 6.07% H; 9.91% N

EXAMPLE 876-Fluoro-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehemifumarate (A) 7-(3-Chloropropoxy)indole

To a stirred suspension of sodium hydride (0.8 g, 17 mmol of a 50% oildispersion) in dimethylformamide (20 ml), under nitrogen, was addeddropwise 7-hydroxyindole (2.1 g, 15.7 mmol) in dimethylformamide (20ml). After complete addition, the reaction was stirred at ambienttemperature for 0.5 hour and then cooled to 15° C. To this cooledsolution was added, dropwise, 1-bromo-3-chloropropane (2.5 g, 15.7 mmol)in dimethylformamide (5 ml). The reaction was then stirred at ambienttemperature for 16 hours. The reaction was poured into water, and theaqueous suspension extracted with ethyl acetate. The ethyl acetate waswashed with water, dried (MgSO₄), and the solvent was concentrated toafford a dark brown oil. Following flash chromatography on silica gel,7-(3-chloropropoxy)indole was obtained as a colorless oil, 1.0 g.

ANALYSIS: Calculated for C₁₁H₁₂ClNO: 63.01% C; 5.77% H; 6.68% N; Found:63.25% C; 5.61% H; 6.65% N

(B)6-Fluoro-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehemifumarate

A stirred mixture of 7-(3-chloropropoxy)-1H-indole (3.5 g, 17 mmol),6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 17 mmol), K₂CO₃(2.3 g) acetonitrile (60 ml) was refluxed for 11 hours. The reaction waspoured into water, and the aqueous mixture was extracted with ethylacetate. The ethyl acetate was washed with water, dried (MgSO₄), and thesolvent was concentrated to afford a dark oil. The oil was flashchromatographed on silica gel. Upon concentration of the appropriatefractions, 3.0 g of a white, foamy substance was obtained. The substancewas dissolved in ethyl acetate (75 ml) and fumaric acid (0.97 g, 83mmol) was added. The mixture was briefly heated to reflux, and thenstirred at ambient temperature for 1.5 hours. The resultant insolublewhite fumarate salt was collected and afforded 4.2 g of product.Recrystallization of the salt from dimethylformamide yielded 3.1 g (36%)of6-fluoro-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehemifumarate as a white solid, m.p.=213°-215° C.

ANALYSIS: Calculated for C₂₅H₂₆FN₃O₄: 66.50% C; 5.80% H; 9.31% N; Found:66.23% C; 6.14% H; 9.39% N

EXAMPLE 886-Fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0g, 45 mmol), K₂CO₃ (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) andacetonitrile (200 ml) was refluxed for 3 hours. The reaction was pouredinto H₂O and 7.1 g of a beige solid was collected. The filtrate wasextracted with dichloromethane, and after concentration an additional6.7 g of crude solid was harvested. The solids were combined andtriturated with refluxing ethyl acetate to afford 8.0 g of6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as anoff-white solid. A sample (4.0 g) was recrystallized from ethanol-water(with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a whitesolid, m.p.=140°-142° C.

ANALYSIS: Calculated for C₁₅H₁₉FN₂O₂: 64.73% C; 6.88% H; 10.06% N;Found: 64.79% C; 6.97% H; 10.03% N

EXAMPLE 896-Fluoro-3-[1-(2-pyrimidinoxy)propyl]-4-piperidinyl]-1,2-benzisoxazolefumarate

To a stirred suspension of6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole (3.6 g,13 mmol) in tetrahydrofuran (50 ml) was added dropwise, potassiumbistrimethylsilylamide (2.6 g, 13 mmol) dissolved in tetrahydrofuran (20ml). After complete addition, the reaction was stirred at ambienttemperature for 5 min, and then 2-chloropyrimidine (1.6 g, 14 mmol) wasadded. The reaction was stirred at ambient temperature for 4 hours, andTLC at this time indicated an incomplete reaction. An additionalquantity of the base (0.5 g) was added, and the reaction was allowed toproceed at ambient temperature for 14 additional hours. The reaction waspoured into water and the aqueous mixture was extracted withdichloromethane. The extract was washed (H₂O), dried (K₂CO₃), and thesolvent was concentrated to afford a wet solid. The solid was trituratedwith diethyl ether and the product that separated was collected to yield1.0 g of the starting alcohol. The filtrate was then concentrated toafford 3.8 g of a waxy, yellow solid. This material was combined with2.6 g from another run and the combined sample flash chromatographed onsilica gel, eluting first with ethyl acetate and then with 8%diethylamine-ethyl acetate. Concentration of the appropriate fractionsafforded 3.0 g of the desired compound as a yellow solid. The solid wasconverted to a fumarate salt with fumaric acid in acetone, and thenreversed to its free base. It was combined with another sample and thecombined sample (3.8 g) chromatographed on silica gel on HPLC (4.5%methanol-dichloromethane as eluent). Concentration of the appropriatefractions yielded 1.6 g of a yellow solid. A fumarate salt was preparedto yield 2.1 g (16%) of6-fluoro-3-[1-[(2-pyrimidinoxy)-propyl]-4-piperidinyl]-1,2-benzisoxazolefumarate, m.p.=184°-186° C.

ANALYSIS: Calculated for C₂₃H₂₅FN₄O₆: 58.47% C; 5.33% H; 11.86% N;Found: 58.52% C; 5.34% H; 11.80% N

EXAMPLE 906-Aceto-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan(A) 6-aceto-2-mesyloxymethyl-1,4-benzodioxan

6-Aceto-2-hydroxymethyl-1,4-benzodioxan (3.39 g, 16.3 mmol) wasdissolved in trichloromethane (100 ml). Triethylamine (2.5 g) was addedto mesylchloride (2.5 g, 1.35 eq) at 0° C. The mixture was stirred for 2hours at room temperature. The mixture was then diluted, washed with anice/dilute hydrochloric acid mixture (150 ml), washed with sodiumbicarbonate and brine, dried over magnesium sulfate, and concentrated toyield 5.6 g. Following chromatography on a SiO₂ column, 3.64 g (78%yield) of 6-aceto-2-mesyloxy-methyl-1,4-benzodioxan were obtained.

(B)6-aceto-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0g, 3.6 mmol), K₂CO₃ (2 g, 14.5 mmol) and6-aceto-2-mesyloxymethyl-1,4-benzodioxan (3.5 g, 12 mmol) inacetonitrile (100 ml) was heated at reflux for 3 hours. At the end ofthe reaction the solvent was removed on a rotary evaporator. The residuewas extracted into dichloromethane (350 ml) and the insolubles werefiltered off. The dichloromethane solution was concentrated and thecrude oil was purified by flash chromatography. The product thusobtained weighed 3.38 g (59%). Recrystallization from ethanol gave6-aceto-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxanas light yellow crystals (3.2 g), m.p.=122°-123° C.

ANALYSIS: Calculated for C₂₃H₂₃FN₂O₄: 67.31% C; 5.65% H; 6.83% N; Found:67.24% C; 5.50% H; 6.75% N

EXAMPLE 912-4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0g, 3.6 mmol), K₂CO₃ (2.45 g, 17.7 mmol),2-methanesulfonyloxymethyl-1,4-benzodioxan (3.35 g, 13.7 mmole) inacetonitrile (100 ml) was heated at reflux for 12 hours. At the end ofthe reaction, the insolubles were filtered and rinsed withdichloromethane. The organic solution was concentrated. The crude oilwas purified by flash chromatography on a silica gel column. Thefractions containing the pure product were pooled and concentrated to alight yellow oil (3.94 g, 74%). Crystallization from ethanol andpetroleum ether gave2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxanas off-white crystals, 2.22 g, m.p.=122°-123° C.

ANALYSIS: Calculated for C₂₁H₂₁FN₂O₃: 68.47% C; 5.75% H; 7.60% N; Found:68.33% C; 5.75% H; 7.51% N

EXAMPLE 922-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-benzodioxan(A) 2-mesyloxyethyl-1,4-benzodioxan

To the compound 2-hydroxyethyl-1,4-benzodioxan (11.96 g) indichloromethane (450 ml) was added triethylamine (0.12 mol, 10 ml).Mesylchloride (9.2 g) was then added dropwise and the reaction mixturewas stirred for one hour at room temperature. After completion of thereaction, the solution was washed with water, brine, and concentrated toan oil, which was purified by chromatography on silica gel to yield2-mesyloxyethyl-1,4-benzodioxan, 17.08 g.

(B)2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,4-benzodioxan

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 21mmol), K₂CO₃ (3.5 g, 25.4 mmol) and 2-mesyloxyethyl-1,4-benzodioxan (5.5g, 21.3 mmol) acetonitrile (250 ml) was heated at reflux for 3.5 hours.At the end of the reaction, insolubles were filtered. The solid waswashed with dichloromethane (200 ml). The solutions were combined andevaporated to an oil. This crude oil was purified by flashchromatography on a silica gel column. The material thus obtained wascrystallized from ethanol. The2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,4-benzodioxancrystals were collected and weighed 3.8 g, 48%, m.p.=112°-113° C.

ANALYSIS: Calculated for C₂₂H₂₃FN₂O₃: 69.09% C; 6.06% H; 7.32% N; Found:69.17% C; 6.02% H; 7.31% N

EXAMPLE 936-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-tetralone(A) 6-(3-chloropropoxy)-7-methoxy-1-tetralone

A mixture of 6-hydroxy-7-methoxy-1-tetralone (J. Org. Chem., 1985, 50,4937) (1.5 g, 7.8 mmol), K₂CO₃ (1.7 g, 12.3 mmol), and acetone (30 ml)was stirred at reflux under nitrogen for 45 minutes. The reaction wascooled to ambient temperature and a solution of 1-bromo-3-chloropropane(1.9 g, 12.1 mmol) dissolved in 8 ml acetone was dripped into themixture. After total addition, the reaction was heated to reflux andstirred under nitrogen for 21 hours. The reaction was cooled to ambienttemperature and filtered. The filter cake was washed well with acetoneand the filtrate was concentrated to yield 2.0 g6-(3-chloropropoxy)-7-methoxy-1-tetralone as an amber oil.

(B)6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-tetralone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (0.78 g, 3.6mmol), K₂CO₃ (0.60 g, 4.1 mmol), KI (100 mg),6-(3-chloropropoxy)-7-methoxy-1-tetralone (0.87 g, 3.2 mmol), andacetonitrile (50 ml) was stirred at reflux under nitrogen for 17 hours.The cooled reaction was poured into 100 ml of water and the aqueousmixture was extracted with ethyl acetate. The ethyl acetate extract waswashed with brine, dried with MgSO₄ and concentrated to yield 1.7 g of abrown oil. The oil was purified by preparative HPLC (Waters AssociatesPrep LC/system 500) to afford 1.0 g of a light brown solid. This wascombined with an additional sample (2.3 g total) and recrystallizationfrom ethanol yielded 1.7 g. A subsequent recrystallization from ethanolgave 1.25 g (36%) of6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-tetraloneas a beige powder, m.p.=129°-131° C.

ANALYSIS: Calculated for C₂₆H₂₉FN₂O₄: 69.01% C; 6.46% H; 6.19% N; Found:68.77% C; 6.43% H; 6.16% N

EXAMPLE 94N-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone(A) N-(3-chloropropyl)-2-benzoxazolinone

To a stirred suspension of sodium hydride (7.8 g, 160 mmol,ether-washed) in dimethylformamide (75 ml) was added dropwise undernitrogen, 2-benzoxazolinone (20.0 g, 150 mmol) dissolved indimethylformamide (150 ml). After complete addition the reaction wasstirred at ambient temperature for 30 min, and then it was cooled to −5°C. with an ice-acetone bath. A solution of 3-chloro-1-bromopropane (46.6g, 300 mmol) in dimethylformamide (50 ml) was added dropwise(temperature never exceeded 0° C.). The reaction was allowed to reachambient temperature and was stirred for 16 hours. The reaction waspoured into water, and the aqueous mixture was extracted with ethylacetate. The ethyl acetate was washed with water, dried (MgSO₄), and theextract concentrated to afford 21.9 g of a brown solid. The solid wasrecrystallized from toluene-hexane to affordN-(3-chloropropyl)-2-benzoxazolinone as large needles, 15.6 g,m.p.=264°-266° C.

(B) N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone

A mixture of N-(3-chloropropyl)-2-benzoxazolinone (8.5 g, 40 mmol),polyphosphoric acid (100 g), and acetic acid (2.4 g, 2.3 ml, 40 mmol),was stirred and heated at 100° C. for 2 hours. The hot solution waspoured into ice-water to deposit a yellow gum. The mixture was extractedwith dichloromethane, and insolubles were filtered. The dichloromethaneextract was washed with water, dried (K₂CO₃), and concentrated to afford6.4 g of a slightly green solid. This was recrystallized from ethanol(95%) to yield N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone as a brownsolid, 3.5 g, m.p.=100°-103° C.

(C)N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9mmol), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 9 mmol),K₂CO₃ (3.6 g), a few crystals of KI, and acetonitrile (50 ml) wasstirred and refluxed for 13 hours. The reaction was poured into water,and a dark, brown solid that separated was collected to afford 3.3 g ofcrude product. The solid was chromatographed on a Waters Prep 500 HPLC.Concentration of appropriate fractions afforded 2.3 g of a yellow solid,and recrystallization from ethyl acetate yielded 1.2 g (31%) ofN-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-6-acetyl-2-benzoxazolinone,m.p.=152°-154° C.

ANALYSIS: Calculated for C₂₄H₂₄FN₃O₄: 65.89% C; 5.53% H; 9.61% N; Found:65.67% C; 5.48% H; 9.52% N

EXAMPLE 95N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (6.44 g, 29.1mmole), K₂CO₃ (6.4 g, 46 mmol), N-(3-bromopropyl)phthalimide (8.4 g, 31mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. Theinsolubles were filtered. The solvent was removed at reduced pressureand the residue was purified by silica gel column chromatography to giveN-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimideas a white solid. Recrystallization from ethanol yielded 9.8 g (83%) ofoff-white crystals, m.p.=129°-130° C.

ANALYSIS: Calculated for C₂₃H₂₂FN₃O₃: 67.89% C; 5.44% H; 10.31% N;Found: 67.49% C; 5.38% H; 10.13% N

EXAMPLE 961-(3-Aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride

A mixture ofN-[3-[4-(6-fluoro-1,2-benzisoxazol-3-1-piperidinyl]propyl]phthalimide(8.5 g, 21 mmol), hydrazine monohydrate (1.5 g, 30 mmol) in methanol (60ml) was heated at reflux for 2 hours. At the end of the reaction,methanol was removed to leave a crude solid. To this was added water (60ml), then the mixture was acidified with HCl to pH 1. The insolubleswere filtered with the aid of a pad of Celite. The aqueous solution wasbasified with 50% N;aOH, (pH 13), then extracted with dichloromethane.The combined dichloromethane solution was welded with brine, then driedto a colorless oil (4.5 g). The analytical sample (1.5 g) was preparedby treating the oil with HCl in ethanol at 0° C. The1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride was obtained as white crystals, 2.03 g, m.p.=231°-234°C.

ANALYSIS: Calculated for C₁₅H₂₀FN₃O.2HCl: 51.44% C; 6.33% H; 12.00% N;Found: 51.35% C; 6.49% H; 11.90% N

EXAMPLE 97cis-2-[3-[4-(6-Fluoro-1,2-benzioxazol-3-yl)-1-piperidinyl]propyl]hexahydro-1H-isioindole-1,3-dionehydrochloride

A mixture of1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.01 g,10.8 mmol) and cis-1,2-cyclohexane-dicarboxylic anhydride (1.9 g, 12.3mmol) in dry pyridine (30 ml) was heated at reflux for 16 hours. Thedark brown solution was concentrated to dryness on a rotary evaporator.The crude residue was purified twice by flash chromatography over asilica gel column. The pure product thus obtained weighed 2.5 g (67%).This was converted to the hydrochloride salt by treatment with HCl inethanol (50 ml). Thecis-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-hexahydro-1H-isoindole-1,3-dionehydrochloride crystals so obtained weighed 3.0 g, m.p.=242°-245° C.

ANALYSIS: Calculated for C₂₃H₂₈FN₃O₃.HCl: 61.14% C; 6.50% H; 9.34% N;Found: 61.32% C; 6.32% H; 9.27% N

EXAMPLE 98N-[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.5 g, 25mmol), 4-bromobutylphthalimide (8.0 g, 28.3 mmol, 1.13 eq), K₂CO₃ (4.55g, 32mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. Atthe end of the reaction, the mixture was filtered. The insolubles werewashed with dichloromethane (200 ml). The organic solution wasconcentrated gradually to allow crystallization. The crude crystals (5.9g) were collected. The mother liquor was concentrated to a solid (5.5g). Purification was by flash chromatography over a silica gel column.The product (3.8 g) thus purified was recrystallized from ethanol (70ml) to give 2.48 g ofN-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimideas white crystals, m.p.=144°-146° C.

ANALYSIS: Calculated for C₂₄H₂₄FN₃O₃: 68.39% C; 5.74% H; 9.97% N; Found:68.34% C; 5.74% H; 9.84% N

EXAMPLE 99 1-(4-Aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride

A mixture ofN-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinyl]butyl]phthalimide(6.9 g, 16.4 mmol) and hydrazine monohyrate (1.64 g, 32.8 mmol) inmethanol (70 ml) was heated at reflux for 3 hours. At the end of thereaction, methanol was removed to leave a crude solid. This wasdissolved in water and acidified with HCl to pH 2. The insolubles werefiltered. The aqueous solution was basified with 50% N;aOH, and thenextracted with dichloromethane. The dichloromethane solution was washedwith water and brine, and then dried over MgSO₄. The solvent was removedto a colorless oil: 4.48 g. This oil was treated with 2.5 equivalents ofHCl in ethanol. The solid was collected. Recrystallization from ethanol(65 ml) and methanol (20 ml) gave 2.0 g of1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride as white crystals, m.p.=234°-237° C.

ANALYSIS: Calculated for C₁₆H₂₂FN₃O₃.2HCl: 52.75% C; 6.64% H; 11.53% N;Found: 52.37% C; 6.59% H; 11.07% N

EXAMPLE 100cis-2-[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]hexahydro-1H-isoindole-1,3-dionehydrochloride

A mixture of1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g,16.1 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (3.23 g, 21mmol) in pyridine (45 ml) was heated at reflux for 8 hours. At the endof the reaction, pyridine was removed to dryness. The crude product waspurified on a silica gel column. The material thus obtained weighed 3.18g (45%) as a clear oil. This oil was dissolved in ethanol (15 ml), thenwas treated with HCl in ethanol (45 ml). Crystallization took place uponcooling. The crystals were collected, 3.2 g, m.p.=229°-231° C.

ANALYSIS: Calculated for C₂₄H₃₀FN₃O₃.HCl: 62.13% C; 6.73% H; 9.06% N;Found: 61.79% C; 6.68% H; 8.92% N

EXAMPLE 1011-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]ethanone(A) 1-[4-[(3-chloropropyl)thio]-3-methoxyphenyl]ethanone

A mixture of 1-(4-thio-3-methoxyphenyl)ethanone (10.0 g, 54.9 mmol),potassium carbonate (9.0 g, 65.1 mmol), and acetone (100 ml) was stirredat reflux under nitrogen for 30 minutes. The reaction was cooled toambient temperature and a solution of 1-bromo-3-chloropropane (6.5 ml,9.5 g, 60.4 mmol) dissolved in acetone (25 ml) was dripped into thereaction. After complete addition, the reaction was heated to reflux andstirred under nitrogen for 17 hours. After the reaction was carried tosubstantial completion, the reaction mixture was filtered and theresulting filter cake was washed with acetone. The filtrate wasconcentrated to provide an amber oil. A small sample was solidified bytrituration with hot cyclohexane to provide1-[4-[(3-chloropropyl)thio]-3-methoxyphenyl]ethanone as a yellow solid,11.7 g, m.p.=53°-55° C.

(B)1-[4-[[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6mmol), 1-[4-[(3-chloropropyl)-thio]-3-methoxyphenyl]ethanone (3.5 g,13.6 mmol), K₂CO₃ (2.3 g, 16.6 mmol), KI (200 mg) and CH₃CN (100 ml) wasstirred at reflux under nitrogen for 7.5 hours and then was left atambient temperature for 65 hours. The reaction was poured into water andthe aqueous mixture was extracted with ethyl acetate. The ethyl acetateextract was washed twice with water, once with brine and dried overMgSO₄. The solvent was removed in vacuo to afford 6.8 g of a light brownoil. The sample was purified by flash chromatography. Concentration ofappropriate fractions yielded 3.0 g. Recrystallization from ethanolprovided 2.4 g (41%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]ethanoneas a beige solid, m.p.=93°-95° C.

ANALYSIS: Calculated for C₂₄H₂₇FN₂O₃S: 65.14% C; 6.15% H; 6.33% N;Found: 64.66% C; 6.17% H; 6.26% N

EXAMPLE 1024-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-(2′-methoxyphenyl)butylpiperidinemaleate (A) 2-(4-bromobutyl)anisole

2-Bromoanisole (2.0 g, 1.07 mmol) in tetrahydrofuran (20 ml) was cooledto −78° C. under nitrogen and secondary butyllithium (1.3M, 10 ml, 1.3eq) was charged into the resulting solution for two hours. The solutionwas quenched with 1,4-dibromobutane (3.2 g) and allowed to stir atambient temperature overnight. The mixture was diluted with ethylacetate, washed with water and brine, and concentrated to an oil.Following chromatography on a SiO₂ column, 2.4 g of2-(4-bromobutyl)anisole were obtained.

(B)4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2′-methoxyphenyl)butylpiperidinemaleate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.36 g, 10.7mmole), K₂CO₃ (2 g, 14.5 mmol) and 2-(4-bromobutyl)anisole (2.4 g, 10mmol) in acetonitrile (100 ml) was heated at reflux for 2.5 hours. Atthe end of reaction, the solvent was removed The residue was extractedinto dichloromethane (200 ml) and filtered. The dichloromethane solutionwas concentrated. The crude oil obtained was purified on a flashchromatography column. The material thus purified was a light yellow oil(2.73 g, 53%). This oil was dissolved in ethanol and treated with maleicacid (607 mg, 1.0 eq) in ethanol. The4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2′-methoxyphenyl)butylpiperidinemaleate crystals formed on concentration and subsequent cooling to 0° C.These were collected and dried to yield 2.05 g, m.p.=132°-133° C.

ANALYSIS: Calculated for C₂₃H₂₇FN₂O₂.C₄H₄O₄: 65.05% C; 6.27% H; 5.62% N;Found: 65.25% C; 6.30% H; 5.70% N

EXAMPLE 1031-[4-(1,3-Dithian-2-yl)ethyl]phenyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)butylpiperidine(A) 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene

To the compound p-bromoacetophenone (36.85 g, 185 mmol) intrichloromethane (300 ml) was added 1,3-propanedithiol (25 g, 230 mmol)and boron trifluoride etherate (3 ml). The resulting mixture was stirredat room temperature for 48 hours. The mixture was diluted withdichloromethane (500 ml), washed twice with 10% sodium hydroxide (200ml), water, and brine, and then dried (Na₂SO₄). The product wasconcentrated to an oil. A portion was stirred with ether (100 ml) and acrystalline product was formed. The crystalline product was recovered byfiltration and purified by recrystallization to yield4-bromo-1-(1,3-dithian-2-yl)ethylbenzene.

(B) 4-(4-bromobutyl)-1-(1,3-dithian-2-yl)ethylbenzene

A solution of 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene (27.2 g, 94 mmol)in tetrahydrofuran (200 ml) was charged with sec-butyllithium (99 ml,1.3M in cyclohexane, 0.13 mole) dropwise at −78° C. under nitrogen. Themixture was stirred at ambient temperature for 1.5 hours, and thenquenched with 1,4-dibromobutane (42 g, 0.2 mole). After being stirredfor 3 hours, the mixture was poured into ethyl acetate, and then washedwith water and brine. The organic solution was then dried (Na₂SO₄) andconcentrated to an oil. The crude product was purified by flashchromatography over a silica gel column. The4-(4-bromobutyl)-1-(1,3-dithian-2-yl)-ethylbenzene thus purified was alight oil, 22.3 g.

ANALYSIS: Calculated for C₁₅H₂₁BrS₂: 52.17% C; 6.13% H; Found: 52.60% C;6.25% H

(C)1-[4-(1,3-dithian-2-yl)ethyl]phenyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)butylpiperidine

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.4 g, 24.5mmol), K₂CO₃ (4.2 g, 30 mmol),4-(4-bromobutyl)-1-(1,3-dithian-2-yl)ethylbenzene (8.5 g, 24.6 mmol) inacetonitrile (200 ml) was heated at reflux for 2.5 hours. At the end ofthe reaction, the mixture was filtered and the solvent was concentrated.The crude (13 g) was purified by flash chromatography over a silica gelcolumn. The material thus purified (8.67 g; 72%) was recrystallized fromethanol (50 ml) and hexane (100 ml) to afford 6.6 g of1-[4-(1,3-dithian-2-yl)ethyl]phenyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)butylpiperidineas light yellow crystals, m.p.=108°-110° C.

ANALYSIS: Calculated for C₂₇H₃₃FN₂OS₂ 66.91% C; 6.86% H; 5.78% N; Found:66.72% C; 6.76% H; 5.71% N

EXAMPLE 1041-[4-(4′-Acetophenyl)butyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine

A solution of1-[4-(1,3-dithian-2-yl)ethylphenyl]butyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine(5.6 g, 11.6 mmol), water (5 ml), and methanol (30 ml), in acetone (50ml), was treated with mercury (II) perchlorate trihydrate (5 g, 1.1 eq.)at room temperature. After 30 minutes, the reaction was completed. Thesolids were filtered, and the solvent was removed on a rotaryevaporator. The crude product was dissolved in ethyl acetate (500 ml)and washed with water, brine, then dried over Na₂SO₄. The solvent wasremoved to give a crude oil. The purification was by flashchromatography over a silica gel column. The oil thus obtained (2.67 g,50%) was combined with 1.1 g of oil prepared in the same fashion.Crystallization from ethanol (10 ml) and hexane (20 ml) yielded1-[4-(4′-acetophenyl)butyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidineas off-white crystals, 2.32 g, m.p.=85°-86° C.

ANALYSIS: Calculated for C₂₄H₂₇FN₂O₂: 73.07% C; 6.90% H; 7.10% N; Found:72.68% C; 7.05% H; 7.09% N

EXAMPLE 1051-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-methoxy-phenyl]ethanone

To a stirred suspension of sodium hydride (0.37 g, 7 mmol of a 50% oildispersion) in dimethylformamide (20 ml) was added, dropwise,1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-hydroxyphenyl]ethanone(2.9 g, 7 mmol) dissolved in dimethylformamide (25 ml). The reaction wasstirred at ambient temperature for 15 minutes, and then it was cooledwith an ice bath to about 5° C., whereupon methyl iodide (1.0 g, 7 mmol)in dimethylformamide (1 ml) was added dropwise. The reaction was stirredat ambient temperature for 30 min, and then water was added. Theresulting aqueous mixture was extracted with ethyl acetate, the extractwashed with water, dried (MgSO₄), and the solvent was concentrated toafford 4.9 g of a brown oil, which solidified on standing. The solid wasflash chromatographed on silica gel. The appropriate fractions wereconcentrated to yield 2.7 g of product as a yellow solid.Recrystallization from toluene-hexane yielded 2.0 g (67%) ofanalytically pure1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-methoxyphenyl]ethanoneas a yellow solid, m.p.=96°-98° C.

ANALYSIS: Calculated for C₂₄H₂₈FN₃O₃: 67.75% C; 6.63% H; 9.88% N; Found:67.93% C; 6.72% H; 9.80% N

EXAMPLE 106(2,4-Difluorophenyl)-[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxalate

In a 1 liter round bottom flask, a solution ofethyl-N-benzyl-3-pyrrolidone carboxylate (21.8 g, 11.7 mmol) in 140 mlof 6N HCl was heated at reflux for 2.5 hours. The solution was cooledand the solvent was removed to dryness with a vacuum pump. The residuewas then treated with thionyl chloride (100 ml) for 16 hours at roomtemperature. After the reaction, the excess thionyl chloride was vacuumstripped to dryness (60° C., 4 hours). To the residue in the flask wasadded 1,3-difluorobenzene (30 g, 26 mmol) followed by aluminum chloride(25 g, 18.7 mmol) in portions at room temperature. When the mixtureturned homogeneous (in about 10 minutes) it was then heated at 55° C.for 1 hour. After the reaction was complete, excess 1,3-difluorobenzenewas removed under reduced pressure. The residue was partitioned betweenice/water and dichloromethane (700 ml) and basified with 50% NaOHsolution to pH 10. The dichloromethane solution was washed with waterand brine, then dried over anhydrous MgSO₄. The solvent was stripped andthe crude oil (31 g) was purified by flash chromatography over a silicagel column. The pure product thus obtained weighed 26 g (74%) as ayellow oil. An analytical sample was prepared by dissolving 4.2 g of theoil in ethanol and treating with an ethanol solution of oxalic acid(1.33 g, 14.8 mmol). To the mixture was added ether dropwise to causecrystallization. Recrystallization from ethanol and ether gave 2.63 g of(2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxalateas white crystals, m.p.=114°-116° C.

ANALYSIS: Calculated for C₂₀H₁₉FNO₅: 61.38% C; 4.89% H; 3.58% N; Found:61.16% C; 4.80% H; 3.60% N

EXAMPLE 1076-Fluoro-3-[1-phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazole fumarate(A) (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime

To the compound(2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone (22 g) in95% ethanol (350 ml) and water (100 ml) was added NH₂OH.HCl (10.1 g) andammonium acetate (12.7 g, 2.1 eq). The resulting mixture was refluxedfor 3.5 hours. The mixture was then allowed to stir at room temperaturefor 24 hours. The reaction mixture was concentrated to remove ethanol,poured into water (500 ml), and extracted with dichloromethane (500 ml).This was followed by washing with water, brine, and drying overmagnesium sulfate. The product was concentrated to an oil and purifiedby column chromatography to yield 12 g of(2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime.

(B) 6-fluoro-3-[1-(phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazolefumarate

A mixture of(2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime(10.8 g, 34.2 mmol), potassium hydroxide (10 g), water (100 ml), andethanol (100 ml) was heated at reflux for 2 hours. At the end of thereaction, the solution was cooled and ethanol was removed on a rotaryevaporator. The aqueous mixture was diluted with water (100 ml) thenextracted with dichloromethane (500 ml). The organic solution was washedwith brine and dried over anhydrous MgSO₄. The solution was concentratedto an oil (9.8 g). The crude product was purified by flashchromatography over a silica gel column. The product thus obtainedweighed 4.46 g (44%) as a light yellow oil. The oily product wasdissolved in ethanol, and then treated with a solution of fumaric acid(1.73 g, 1.0 eq) in ethanol. Crystallization took place slowly with theaddition of isopropyl ether. Recrystallization from ethanol (15 ml) gave4.6 g of 6-fluoro-3-[1-(phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazolefumarate as white crystals, m.p.=142°-144° C.

ANALYSIS: Calculated for C₂₂H₂₁FN₂O₅: 64.07% C; 5.13% H; 6.81% N; Found:64.11% C; 5.05% H; 6.89% N

EXAMPLE 108 (E)-1-[4-[(4-bromo-2-butenyl)oxy]-3-methoxyphenyl]ethanone

A mixture of 4-hydroxy-3-methoxyacetophenone (10 g, 59 mmol), K₂CO₃ (10g, 1.2 q) and 1,4-dibromo-2-butene (>95% trans, Aldrich, 18 g, 1.2 eq)in acetone (500 ml) was heated at 55° C. for 3 hours. At the end of thereaction, the solvent was concentrated. The crude product was extractedinto dichloromethane (750 ml) and the insolubles were filtered; then thesolution was concentrated again to an oil. Purification on a silica gelcolumn (SiO₂, 100 g, eluted with dichloromethane) yielded 7.25 g (40%)of white solid. Recrystallization from ether gave analytically pure(E)-1-[4-[(4-bromo-2-butenyl)oxy]-3-methoxyphenyl]ethanone (3.91 g),m.p.=71°-72° C.

ANALYSIS: Calculated for C₁₃H₁₅BrO₃: 52.19% C; 5.50% H; Found: 52.12% C;4.94% H;

EXAMPLE 109 4-(3-Chlogropropoxy)-3-methoxybenzaldehyde

A mixture of vanillin (30.4 g, 200 mmol), K₂CO₃ (27.6 g) and acetone(150 ml) was stirred and refluxed for 0.5 hours. Heating was removed and1-bromo-3-chloropropane (40.8 g, 260 mmol) in acetone was addeddropwise. The reaction was stirred and refluxed for 16 hours, and thenit was poured into water. The aqueous mixture was extracted with diethylether, the extract was dried (MgSO₄), and the solution was concentratedto afford an oil, which upon evacuation solidified to a white solid(50.2 g). An 8.0 g sample was flash chromatographed on silica gel with50% ethyl acetatehexane as eluent. Concentration of appropriatefractions gave 2.7 g (37%) of 4-(3-chloropropoxy)-3-methoxybenzaldehydeas a white solid, m.p.=53°-55° C.

ANALYSIS: Calculated for C₁₁H₁₃ClO₃: 57.78% C; 5.73% H; Found: 57.21% C;5.52% H;

EXAMPLE 110 6-Fluoro-3-(3-pyrrolidinyl)-1,2-benzisoxazole hydrochloride

A mixture of 3-(6-fluoro-1,2-benzisoxazol-3-yl)-1-pyrrolidinylcarboxylicacid ethenyl ester (5.1 g, 18.4 mmol, hydrochloric acid (5 ml), andisopropyl alcohol (50 ml) was heated at reflux for 3.5 hours. At the endof the reaction, the solvent was reduced to about 30 ml on a rotaryevaporator and the mixture was cooled to 0° C. for 2 hours. The crystalswere collected by filtration and rinsed with cold isopropyl alcohol. The6-fluoro-3-(3-pyrrolidinyl)-1,2-benzisoxazole hydrochloride productweighed 3.09 g (69%), m.p.=225°-227° C.

ANALYSIS: Calculated for C₁₁H₁₁FN₂O.HCl: 54.44% C; 4.99% H; 11.54% N;Found: 54.35% C; 4.99% H; 11.38% N

EXAMPLE 1111-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylaminol-3-hydroxy-phenyl]ethanone

A mixture ofN-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl-6-acetyl-2-benzoxazolinone(6.0 g, 14 mmol) and 10% aqueous sodium hydroxide (50 ml) was stirredand refluxed for 40 minutes. Water was added and the reaction was madeacidic with 5% hydrochloric acid. Saturated Na₂CO₃ was added untileffervescence ceased. The aqueous mixture was extracted withdichloromethane. The dichloromethane extract was washed (water), dried(K₂CO₃) and concentrated to afford 2.6 g of a tacky solid. The crudesolid was treated with saturated NaHCO₃, and extracted intodichloromethane. The dichloromethane was washed (brine and then water),and dried (MgSO₄). The organic extract was then concentrated to yield2.4 g of a brown solid, which was combined with another sample to yield5.0 g. This sample was flash chromatographed on silica. A small sample(0.25 g) was recrystallized from toluene to yield1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-hydroxyphenyl]ethanoneas a brownish solid, 0.15 g, m.p.=150°-152° C.

ANALYSIS: Calculated for C₂₃H₂FN₃O₃: 67.14% C; 6.37% H; 10.21% N; Found:67.54% C; 6.58% H; 9.95% N

EXAMPLE 112 1-[3-Acetylamino-4-(3-chloropropoxy)phenyl]ethanone

A stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl]ethanone (7.7 g,40 mmol), K₂CO₃ (5.7 g), 3-chloro-1-bromopropane (8.9 g, 56 mmol), andacetone (100 ml) was refluxed for 16 hours. The reaction was allowed tocool to ambient temperature, and filtered. Concentration of the filtrateyielded 8.5 g of a white solid. The solid was recrystallized fromtoluene and then from ethanol to afford 6.5 g of an off-white solid. A3.3 g sample of this material was flash chromatographed on silica gel.Concentration of the appropriate fractions afforded 2.8 g of a whitesolid. The solid was recrystallized from toluene and then fromethanol-water to yield 2.2 g (51%) of1-[3-acetylamino-4-(3-chloropropoxy)phenyl]ethanone as a white solid,m.p.=124°-126° C.

ANALYSIS: Calculated for C₁₃H₁₆ClNO₃: 57.89% C; 5.98% H; 5.19% N; Found:57.08% C; 5.85% H; 5.13% N

EXAMPLE 113 N-[2-(3-hydroxypropoxy)phenyl]acetamide

A stirred mixture of 2-hydroxyphenylacetamide (10.0 g, 66 mmol), K₂CO₃(6.9 g), 3-bromopropanol (12.8 g, 12 mmol), and acetone (250 ml) wasrefluxed for 16 hours. The reaction mixture was allowed to cool, andthen it was filtered. The filtrate was concentrated to yield 19.0 g of athick, brown oil. The oil was distilled with a Kugelrohr apparatus and11.2 g (82%) of a viscous, orange oil was collected. The oil solidifiedupon standing. An analytical sample was obtained by recrystallizationfrom ethyl acetate to afford the alcohol as an off-white solid,m.p.=78°-80° C.

ANALYSIS: Calculated for C₁₁H₁₅NO₃: 63.14% C; 7.23% H; 6.69% N; Found:63.10% C; 7.32% H; 6.64% N

EXAMPLE 114 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butylbromide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (12 g, 55mmol), K₂CO₃ (13 g) and 1,4-dibromobutane (20 g, 9.3 mmol, 1.7 eq) inacetonitrile (300 ml) was stirred at room temperature overnight. Theinorganic material was filtered. The solution was concentrated to ˜80ml, when crystals crashed out. The product was filtered to yield 14.16 g(73%), m.p.=243°-245° C.

ANALYSIS: Calculated for C₁₆H₂₀BrFN₂O: 54.09% C; 5.67% H; 7.89% N;Found: 54.13% C; 5.52% H; 7.83% N

EXAMPLE 115 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylacetate fumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6mmol), K₂CO₃ (3.5 g, 25 mmol), 2-bromoethyl acetate (4 g, 26.5 mmol) inacetonitrile (50 ml) was heated at reflux for 4 hours. After cooling toroom temperature, the inorganic salts were filtered and washed with DCM(dichloromethane 50 ml). The organic solvent was removed on a rotaryevaporator to give an oil. The oily product was purified on a flashchromatography column (60 g of SiO₂; eluted with MeOH 2%-4% in DCM). Thepure product thus obtained weighed 4.43 g. This oil was dissolved inethanol and treated with a solution of fumaric acid (1.2 g) in ethanol.The salt crystallized out at room temperature to yield 3.44 g (57%),m.p.=154°-155° C.

ANALYSIS: Calculated for C₁₆H₁₉FN₂O₃.C₄H₄O₄: 56.86% C; 5.49% H; 6.63% N;Found: 56.75% C; 5.41% H; 6.54% N

EXAMPLE 116N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]morphine

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) andK₂CO₃ (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for24 hours. The crude mixture was diluted with DCM and filtered. Thesolvent was concentrated to an oil (˜7.1 g). Purification on a silicagel column (55 g, SiO₂, eluted with MeOH:DCM) yielded a solid productweighing 4 g. Recrystallization from hot ethanol yielded 2.1 g (48%),m.p.=131°-132° C.

ANALYSIS: Calculated for C₁₈H₂₄FN₃O₂: 64.84% C; 7.26% H; 12.60% N;Found: 64.80% C; 7.09% H; 12.77% N

EXAMPLE 117N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.15 g, 23.4mmol), K₂CO₃ (4.2 g, 30.4 mmol) and 2-bromoethyl phthalimide (7.13 g, 28mmol) in acetonitrile (250 ml) was heated at reflux for 3.5 hours. Thesolids and solvent were removed. The residue was purified by flashchromatography (SiO₂, 110 g, eluted with 2-4% C;H₃OH:DCM). The productthus obtained weighed 7.8 g (84%). Part of the material wasrecrystallized to give 2.35 g of off white crystals, m.p.=148°-149° C.

ANALYSIS: Calculated for C₂₂H₂₀FN₃O₃: 67.17% C; 5.12% H; 10.68% N;Found: 67.01% C; 5.20% H; 10.76% N

(A)N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimidehydrochloride

To a solution of 8.0 g ofN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimidein dichloromethane/ethanol (150 ml) was added 1M-HCl in ether. The saltcrystallized out rapidly. It was filtered off, washed with ethanol anddried to afford 8.15 g with m.p.=257°-259° C., dec. Recrystallizationprovided 7.20 g of pure white salt, with m.p. unchanged.

ANALYSIS: Calculated for C₂₂H₂₀FN₃O₃.HCl 61.47% C; 4.92% H; 9.77% N;Found: 61.12% C; 5.21% H; 9.58% N

EXAMPLE 118 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylmethyl ether fumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.75 g, 17mmol), K₂CO₃ (3 g, 21.7 mmol), bromoethyl methyl ether (2.84 g, 20.4mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. Thereaction was cooled. The inorganics were filtered and rinsed with DCM.The organic solution was concentrated down to an oil (7 g). Purificationon a flash chromatography column (SiO₂, 45 g; eluted with methanol/DCM)gave a light yellow oil as product (4 g, 87%). This oil was dissolvedinto ethanol and treated with a solution of fumaric acid (1.67 g) inethanol (20 ml). White crystals (5.15 g) were collected, m.p.=157°-158°C.

ANALYSIS: Calculated for C₁₅H₁₉FN₂O₂.C₄H₄O₄: 57.86% C; 5.88% H; 7.10% N;Found: 57.53% C; 5.94% H; 6.94% N

EXAMPLE 119 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butylacetate fumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.5 g, 41mmol), K₂CO₃ (7.2 g, 51 mmol), and 4-bromobutyl acetate (10 g, 51 mmol)in acetonitrile (200 ml) was heated at reflux for 3.5 hours. At the endof the reaction, the solution was cooled and filtered. The inorganicsalt was washed with DCM (50 ml). The organic solvent was removed. Theresidue was purified on a flash chromatography column (packed withSorbsil C30 silica gel, 100 g, eluted with DCM, 1 liter, increasingmethanol from 2 to 4%, 2.51). The material thus purified weighed 12.92 g(89%). A small sample (1.67 g) was dissolved in ethanol and treated with1 equivalent of fumaric acid (580 mg) in ethanol to yield whitecrystals: 1.8 g, m.p.=142°-143° C.

ANALYSIS: Calculated for C₁₈H₂₃FN₂O₃.C₄H₄O₄: 58.66% C; 6.04% H; 6.22% N;Found: 58.56% C; 6.02% H; 6.13% N

EXAMPLE 120 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanolfumarate

A mixture of 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butylacetate (11.5 g, 34.4 mmol), 15% N;aOH (100 ml) and ethanol (100 ml) washeated at reflux for 4 hours. After cooling to room temperature, thebase was neutralized with HCl to pH=7. The solution was concentrateddown to a small volume (˜50 ml), then extracted with DCM. The DCMsolution was washed with brine and dried over MgSO₄. The solvent wasconcentrated to give ˜10 g of crude oil. Purification by flashchromatography (Sorbsil C-30 100 g, eluted with MeOH:DCM, 3 liters)yielded 9.8 g of white solid. The sample for testing was prepared bytreatment of the free base (2.0 g) with fumaric acid (780 mg, 1.0 eq) inethanol. The crystals were collected and dried: 1.5 g, m.p.=131°-132° C.

ANALYSIS: Calculated for C₁₆H₂₁FN₂O₂.C₄H₄O₄: 58.82% C; 6.17% H; 6.86% N;Found 58.81% C; 6.37% H; 6.66% N

EXAMPLE 121 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyldecanoate fumarate

To a solution of4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (2.0 g, 6.84mmol), triethylamine (1.0 g, 10 mmol) in DCM (70 ml) decanoyl chloride(1.7 g, 8.9 mmol) was added dropwise at room temperature. The mixturewas stirred for 1 hour, then was concentrated to a crude solid. Thesolid was extracted into ethyl acetate, and the insoluble salts werefiltered. The solvents were removed. The crude product was purified byflash chromatography (Sorbsil C-30, 30 g, eluted with a mixture of MeOHin DCM). The oil thus obtained (2.5 g, 81%) was converted to a fumaratesalt with fumaric acid (650 mg, 1.0 eq) in ethanol. Crystals werecollected: 1.48 g, m.p.=109°-110° C.

ANALYSIS: Calculated for C₂₆H₃₉FN₂O₃.C₄H₄O₄: 64.04% C; 7.70% H; 4.98% N;Found: 64.30% C; 7.86% H; 4.78% N

EXAMPLE 122 3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyldecanoate fumarate

To a solution3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propanol (1.81 g,6.5 mmol) triethylamine (0.9 g, 9.0 mmol) in DCM (45 ml) was addeddecanoyl chloride (1.5 g, 7.8 mmol) dropwise at room temperature. Themixture was stirred for 20 minutes, then concentrated down to a crudesolid. The solid was extracted into EtOAc (20 ml), and the insolublesalts were filtered. The EtOAc was removed. The crude oil was purifiedby flash chromatography (Sorbsil C-30, 30 g; eluted with MeOH:DCM). Theoil thus obtained (2.54 g, 90%) was converted to a fumarate salt withfumaric acid (670 mg) in ethanol. The crystals collected weighed 1.61 g,m.p.=100°-102° C.

ANALYSIS: Calculated for C₂₅H₂₇FN₂O₃.C₄H₄O₄: 63.52% C; 7.54% H; 5.11% N;Found: 63.63% C; 7.74% H; 5.03% N

EXAMPLE 123N,N-Diethyl-4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butylcarbamate fumarate

To a mixture of4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (1.55 g, 5.3mmol) potassium t-butoxide (750 mg, 6.7 mmol) in THF (100 ml),diethylcarbamyl chloride (900 mg, 6.63 mmol) was added dropwise at roomtemperature. The mixture was stirred for 2 hours, then the solvent wasremoved. The residue was extracted into DCM. The DCM solution was washedwith brine and dried over MgSO₄. The solution was concentrated. Theproduct was purified on a flash chromatography column (SiO₂, 14 g,eluted with 2% MeOH in DCM), to yield 1.84 g of oil. This oil wasdissolved into ethanol (˜5 ml) and treated with a solution of fumaricacid (850 mg, 1.0 eq) in ethanol. Crystallization was induced with asmall volume of isopropyl ether to produce 2.09 g, m.p.=152°-153° C.

ANALYSIS: Calculated for C₂₁H₃₀FN₃O₃.C₄H₄O₄: 59.16% C; 6.75% H; 8.28% N;Found: 59.17% C; 6.84% H; 8.16% N

EXAMPLE 124N-Methyl-4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butylcarbamate fumarate

To a mixture of4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (1.84 g, 6.3mmol), K₂CO₃ (850 mg) in chloroform, methyl isocyanate (448 mg, 7.7 mmoland 360 mg, 6.2 mmol) was added dropwise in two portions. The mixturewas filtered and concentrated to a crude oil. Purification was done on aflash chromatography column (SiO₂, 11 g, eluted with 2% C;H₃OH in DCM)to yield a light yellow oil (2.05 g, 93%). This oil was dissolved intoethanol and treated with a solution of fumaric acid (800 mg, 1.0 eq).Crystallization was induced with drops of isopropyl ether. Weight: 1.36g, m.p.=96°-98° C.

ANALYSIS: Calculated for C₁₈H₂₄FN₃O₃.C₄H₄O₄: 56.76% C; 6.06% H; 9.02% N;Found: 56.27% C; 6.03% H; 8.86% N

EXAMPLE 1252-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,3-dioxanefumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9.1mmol), K₂CO₃ (1.5 g, 10.9 mmol) and bromoethyl-1,3-dioxane (2.1 g, 10.7mmol) in acetonitrile (50 ml) was heated at reflux for 3 hours. At theend, the insolubles were filtered and rinsed with DCM and the filtratewas evaporated down. The crude mixture was purified by flashchromatography over a silica gel column (Sorbsil C-30, 25 g; eluted withDCM and MeOH (1-3%) in DCM). The fractions containing the pure productwere combined and concentrated to give 3.13 g of oil. The oil wastreated with a fumaric acid (1.0 g) ethanol solution. The crystals werecollected: 3.98 g (77%), m.p.=161°-162° C.

ANALYSIS: Calculated for C₁₈H₂₃FN₂O₃.C₄H₄O₄: 58.66% C; 6.04% H; 6.22% N;Found: 58.69% C; 5.96% H; 6.20% N

EXAMPLE 126 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethanolhemifumarate (A)2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl acetate

2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl acetate wasprepared according to Example 115.

(B) 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl-1-piperidinyl]ethanolhemifumarate

2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl-1-piperidinyl]ethyl acetate (10.58g, 34.6 mmol), 15% N;aOH (100 ml) and ethanol (100 ml) was heated atreflux for 4 hours. The solution was cooled (˜5° C.) and neutralizedwith HCl to pH ˜7. The ethanol was removed under reduced pressure. Theaqueous solution was basified with NaHCO₃ and extracted with DCM (2×200ml). The DCM solution was washed with brine and dried over MgSO₄ andevaporated to give a white solid: 6.88 g (75%). A sample (2.03 g) wasdissolved in ethanol and treated with fumaric acid (660 mg, 1.0 eq).Crystallization was induced with drops of isopropyl ether to yieldoff-white crystals: 1.43 g, m.p.=159°-161° C.

ANALYSIS: Calculated for C₁₄H₁₇FN₂O₂.0.5C₄H₄O₄: 56.62% C; 5.94% H; 8.69%N; Found: 59.55% C; 5.95% H; 8.53% N

EXAMPLE 127 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyldecanoate fumarate

A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylalcohol (1.6 g, 5 mmol) and triethylamine (800 mg, 8 mmol) in chloroform(100 ml) was treated with decanoyl chloride (1.3 g, 7.2 mmol) dropwiseat room temperature. The mixture was stirred for 4 hours. The solventwas removed to leave a crude solid. The solid was dissolved into a smallamount of DCM (15 ml), then was filtered. The solution was concentrated.

The purification was done by flash chromatography over a silica gelcolumn (Sorbsil C-30, 30 g; eluted with MeOH: DCM). The purified oil(2.45 g, 95%) was treated with a fumaric acid (660 mg, 1.0 eq)/ethanolsolution (15 ml). Crystallization was induced by adding drops of ether;yield: 1.97 g, m.p.=109°-110° C.

ANALYSIS: Calculated for C₂₄H₃₅FN₂O₃.C₄H₄O₄: 62.90% C; 7.35% H; 5.24% N;Found: 62.93% C; 7.30% H; 5.14% N

EXAMPLE 128N,N-Diethyl-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylcarbamate fumarate

To a mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethanol (1.6 g, 6mmol) and potassium t-butoxide (850 mg, 7.6 mmol) in THF (100 ml)diethyl carbamyl chloride (1.03 g, 7.5 mmol) was added dropwise at roomtemperature. The mixture was stirred for 4 hours. The reaction mixturewas concentrated to a crude solid. The solid was dissolved in DCM andpurified on a flash chromatography column (Sorbsil C-30, 27 g; elutedwith a MeOH: DCM mixture). The product thus purified as a light oil (2.2g, 91%) was dissolved into ethanol and treated with a fumaric acid (690mg, 1.0 eq)/ethanol solution (15 ml). Crystallization on cooling yielded2.15 g of white crystals, m.p.=133°-135° C.

ANALYSIS: Calculated for C₁₉H₂₆FN₃O₃•C₄H₄O₄: 57.61% C; 6.31% H; 8.76% N;Found: 57.49% C; 6.25% H; 8.54% N

EXAMPLE 1292-[4-[(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]aminehemifumarate (A)N-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl phthalimide

N-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl phthalimidewas prepared according to Example 117.

(B) 2-[4-[(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]aminehemifumarate

A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylphthalimide (4.6 g, 11.7 mmol) and hydrazine monohydrate (1.17 g, 23.4mmol) in methanol (50 ml) was heated at reflux overnight. At the end ofthe reaction, methanol was removed to leave a crude solid. This wasstirred with water (150 ml) and acidified with HCl to pH=2. Theinsolubles were filtered. The aqueous solution was basified with 50%N;aOH then extracted with DCM (2×250 ml). The DCM solution was washedwith brine and dried over MgSO₄. The solvent was removed to produce acolorless oil: 2.12 g. This oil was treated with a solution of fumaricacid (935 mg, 1.0 eq) in ethanol. The salt crystallized out: 0.99 g,m.p.=203°-205° C. A second crop of 0.73 g (m.p.=198°-200° C.) wascollected later.

ANALYSIS: Calculated for C₁₄H₁₈FN₃O•0.5C₄H₄O₄: 59.80% C; 6.27% H; 13.07%N;

EXAMPLE 130 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyldecanamide fumarate

To a mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (1.49 g,5.5 mmol) and triethylamine (1.0 g, 10 mmol) in chloroform (50 ml)decanoyl chloride (1.26 g, 6.6 mmol) was added at room temperature. Themixture was stirred for 3 hours at room temperature. The solvent wasstripped down to a crude mixture. This crude mixture was purified byflash chromatography over a silica gel column (SiO₂, 20 g; eluted with asolution of MeOH (0-3%) in DCM). The fractions containing the pureproduct were pooled and concentrated to give 2.3 g of oil. This oil wasconverted to a fumarate salt by treatment with fumaric acid (655 mg) inethanol. The ethanol was concentrated down to a small volume and 3volumes of isopropyl ether was added. This mixture was stirred overnightto cause crystallization. The solids were collected, weighed: 1.83 g(60.5%), m.p.=108°-110° C.

ANALYSIS: Calculated for C₂₄H₃₆FN₃O₂•C₄H₄O₄: 63.02% C; 7.56% H; 7.87% N;Found: 62.42% C; 7.58% H; 7.66% N

EXAMPLE 131 2-[4-(6-Fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl]ethylacetamide fumarate

A mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.56 g,9.7 mmol) and triethylamine (1.45 g, 14.5 mmol) in DCM (50 ml) wastreated with dropwise addition of acetyl chloride (1.0 g, 12.7 mmol) atroom temperature. The mixture was stirred for 4 hours at roomtemperature. The reaction mixture was diluted with DCM and washed withbrine. The organic solution was dried over MgSO₄ and concentrated to acrude oil. The crude oil was purified by flash chromatography over asilica gel column (SiO₂, 20 g; eluted with (0-2%) CH₃OH in DCM). Thepure product thus obtained weighed 1.36 g (46%). It was converted to afumarate salt by treatment with fumaric acid (517 mg) in ethanol.Recrystallization from ethanol gave white crystals; weight: 1.53 g,m.p.=132°-133° C.

ANALYSIS: Calculated for C₁₆H₂₀FN₃O₂•C₄H₄O₄: 57.00% C; 5.74% H; 9.97% N;Found: 57.05% C; 5.85% H; 9.95% N

EXAMPLE 1322-[[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amino]ethylacetate fumarate

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.0 g,7.6 mmol), K₂CO₃ (1.38 g, 10 mmol) and bromoethyl acetate (1.40 g, 8.3mmol) in acetonitrile (50 ml) was heated at reflux for 4 hours. At theend, the insolubles were filtered off and rinsed with DCM. The solventwas evaporated down. The crude mixture was purified by flashchromatography over a silica gel column (Sorbsil C-30, 30 g; eluted with2% C;H₃OH in DCM, 800 ml). The oil (1.15 g) thus obtained was treatedwith a solution of fumaric acid (358 mg) in ethanol. Crystallization wasinduced by adding drops of ethyl ether, yield: 1.09 g, m.p.=116°-118° C.

ANALYSIS: Calculated for C₁₈H₂₄FN₃O₃•C₄H₄O₄: 56.77% C; 6.06% H; 9.03% N;Found: 56.32% C; 5.97% H; 8.94% N

EXAMPLE 133 Methyl2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl carbamatefumarate

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.0 g,7.6 mmol) and triethylamine (1.0 g, 10 mmol) in DCM (50 ml) was treatedwith methyl chloroformate (860 mg, 9.12 mmol) dropwise at roomtemperature. The mixture was stirred for 1 hour. The reaction mixturewas diluted with DCM and washed with brine. The organic solution wasdried over MgSO₄ and concentrated to a crude oil. The purification wasdone by flash chromatography over a silica gel column (28 g of SorbsilC-30, eluted with DCM and MeOH/DCM). The pure oil thus obtained weighed2.34 g. It was converted to a fumarate salt by treatment with fumaricacid (840 mg, 1.0 eq) in ethanol. Crystallization was induced by addingdrops of isopropyl ether, yield: 2.31 g, m.p.=163°-165° C.

ANALYSIS: Calculated for C₁₆H₂₀FN₃O₃•C₄H₄O₄: 54.92% C; 5.53% H; 9.61% N;Found: 54.49% C; 5.45% H; 9.24% N

EXAMPLE 134Z-2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]hexahydro-1H-isoindole-1,3-dionefumarate

A mixture of1-(2-aminoethyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.77 g,14.3 mmol) and cis-1,2-cyclohexane-dicarboxylic anhydride (2.82 g, 18.2mmol, 1.25 eq) in dry pyridine (50 ml) was heated at 65° C. for 48hours. The dark brown solution was concentrated to dryness on a rotaryevaporator. The crude residue was purified twice by flash chromatographyover a silica gel column (SiO₂, 45 g and 50 g, eluted with DCM and 1%C;H₃OH in DCM). The pure product thus obtained 2.35 g (41%), wasconverted to the fumarate salt by treatment with fumaric acid (660 mg)in ethanol. The crystals after two recrystallizations weighed 1.37 g,m.p.=172°-173° C.

ANALYSIS: Calculated for C₂₂H₂₆FN₃O₃•C₄H₄O₄: 60.57% C; 5.87% H; 8.15% N;Found: 60.40% C; 5.55% H; 7.82% N

EXAMPLE 135(S)-(+)-3-[4-(6-Fluoro-1,2-benzisoxazol3-yl)-1-piperidinyl]-2-methyl-1-propanolfumarate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (7.2 g, 32.7mmol), (S)-(+)-3-bromo-2-methyl-1-propanol (5.0 g, 32.6 mmol),K₂CO₃(7.19 g, 52 mmol) in acetonitrile (250 ml) was heated at refluxovernight. The insolubles were filtered off. The solvent was removed atreduced pressure and the crude residue was purified by silica gelchromatography (SiO₂, 84 g, eluted with 21 of 1% C;H₃OH in DCM) to givethe target compound as an off-white solid (8.83 g, 94%). A sample of 1.7g was converted to the fumarate salt by treatment with fumaric acid (710mg) in ethanol. Recrystallization from ethanol yielded 1.74 g of whitecrystals, m.p.=119°-121° C.

ANALYSIS: Calculated for C₂₀H₂₅FN₂O₆: 58.82% C; 6.17% H; 6.86% N; Found:58.81% C; 6.24% H; 6.76% N

EXAMPLE 1364-(6-Fluoro-1,2,benzisoxazol-3-yl)-1-[3-(1-piperidinyl)propyl]piperidinedifumarate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6mmol), N-(3-chloropropyl)piperidine hydrochloride (4.05 g, 20.4 mmol),K₂, CO₃ (6 g, 43.4 mmol), tetrabutylammonium hydrogen sulfate (phasetransfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) washeated at reflux for 16 hours. The mixture was washed with brine and thelayers were separated. The organic solution was concentrated. The crudeproduct (6.4 g) was purified by flash chromatography over a silica gelcolumn (55 g, sorbsil C-30; eluted with 2% C;H₃OH:0.5% DEA in DCM,1.41). The oil thus purified (4.5 g) was treated with fumaric acid (1.6g) in ethanol. The solid was collected: weight 3.1 g, m.p.178°-181° C.Recrystallization from ethanol yielded 2.28 g of white crystals,m.p.=190°-192° C.

ANALYSIS: Calculated for C₂₀H₂₄FN₃O₂•C₄H₄O₄: 58.22% C; 6.28% H; 7.27% N;Found: 58.39% C; 6.36% H; 7.34% N

EXAMPLE 1371-(3-Dimethylaminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedifumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.05 g, 13.8mmol), 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 21 mmol),K₂CO₃ (6.2 g, 45 mmol), tetrabutylammonium hydrogen sulfate (phasetransfer catalyst, 1.5 g) in acetonitrile (100 ml) and water (50 ml) washeated at 60° C. overnight. The aqueous phase was separated, andacetonitrile was removed at reduced pressure. The residue was extractedinto DCM. The organic solution was washed with H₂O and brine, then driedwith MgSO₄. The solvent was removed and the crude product (4.3 g) wastreated with fumaric acid (1.58 g, 1.0 eq) in dilute ethanol. Thecrystals were collected (2.53 g), m.p.=192°-194° C. Recrystallizationfrom ethanol yielded 2.08 g of white crystals, mp=194°-195° C.

ANALYSIS: Calculated for C₁₇H₂₄FN₃O₂•C₄H₄O₄: 55.86% C; 6.00% H; 7.82% N;Found: 56.11% C; 5.94% H; 7.86% N

EXAMPLE 138(R)-(−)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanolfumarate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (14.5 g, 65mmol), K₂CO₃ (10 g, 72 mmol). (R)-(−)-3-bromo-2-methyl-1-propanol (10 g,65.3 mmol), tetrabutylammonium hydrogen sulfate (1.27 g, phase transfercatalyst) in acetonitrile (300 ml) and H₂O (5 ml) was heated at refluxfor 6 hours. The mixture was cooled and the solvent was removed onrotary evaporator. The residue was extracted into methylene chloride(DCM), and the insolubles were filtered. After concentration of theextract, the crude product was purified by flash chromatography over asilica gel column (SiO₂, 150 g; eluted with DCM, 1 l; 2% C;H₃OH in DCM,1.61). The material thus purified weighed 17 g (89%). The sample fortesting was prepared by treatment of a sample (2.28 g) with fumaric acid(953 mg) in ethanol. The crystals formed slowly upon addition ofisopropyl ether. These were collected and dried: weight 1.84 g,m.p.=114°-115° C.

ANALYSIS: Calculated for C₁₆H₂₁FN₂O₂•C₄H₄O₄: 58.82% C; 6.17% H; 6.86% N;Found: 58.48% C; 6.08% H; 6.57% N

EXAMPLE 1393-[1-[3-[4-(1-Methoxyethyl)-2-hydroxyphenoxyl]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.7 g, 26.0mmol), 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzenemethanol (6.0 g,26.0 mmol), NaHCO₃ (2.4 g, 28.6 mmol), KI(200 mg) and CH₃CN (150 ml) wasstirred at reflux under N₂ for 17 hours. A TLC showed a trace of thealkylating side chain, therefore additional6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (0.6 g, 2.7 mmol) andNaHCO₃ (0.22 g, 2.6 mmol) was added and the reaction was refluxed 3hours longer. The cooled reaction was concentrated and the residue waspartitioned between EtOAc and H₂O. The EtOAc extract was washed with H₂Othen brine and after drying with MgSO₄ the extract was concentrated toyield 11.9 g of a beige oil. The sample was purified by preparative HPLC(Water's Associates Prep LC/System 500 utilizing 2 silica gel columnsand eluting with 5% MeOH—CH₂Cl₂). Concentration of later fractionsafforded 4.2 g of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanol.Concentration of earlier fractions gave 4.0 g of a mixture of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanoland3-[1-[3-[4-(1-methoxyethyl)-2-hydroxyphenoxy]propyl]-4-piperdinyl]-6-fluoro-1,2-benzisoxazole(the latter was apparently formed by the reaction of the former withMeOH on silica gel). The mixture was dissolved in anhydrous Et₂O (330ml) and anhydrous MeOH (100 ml) and ethereal HCl was added. Afterstirring 1.5 hours, anhydrous Et₂O was added and the resultant solid wascollected and dried to yield 2.9 g of a mixture of the respective HClsalts. The solid was suspended in H₂O and was basified with NH₄OH. Theaqueous mixture was extracted with CH₂Cl₂ and the extract was washedwith H₂O, dried with MgSO₄ and concentrated to yield 2.7 g of a lightbeige oil. The oil was purified by preparative HPLC (Water's AssociatesPrep LC/System 500 using 2 silica gel columns and 3% MeOH—CH₂Cl₂ aseluent). Concentration of later fractions yielded 0.5 g of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperdinyl]-propoxy]-3-hydroxy-α-methylbenzenemethanol.Concentration of earlier fractions gave an oil that solidified uponstanding. The product was triturated with heptane and filtered to yield1.2 g of a white powder. The compound was recrystallized from EtOH toprovide 1.1 g (10%) of3-[1-[3-[4-(1-methoxyethyl)-2-hydroxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazoleas clean white crystals m.p.=98°-100° C.

ANALYSIS: Calculated for C₂₄H₂₉FN₂O₄: 67.27% C; 6.82% H; 6.54% N; Found:67.18% C; 6.84% H; 6.54% N

EXAMPLE 1406-Fluoro-3-[1-13-(1H-indol-5-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.6 g, 11.8mmol), K₂CO₃ (1.6 g, 11.6 mmol), KI (200 mg), 5-(3-chloropropoxy)indole(2.2 g, 10.5 mmol) and CH₃CN (100 ml) was stirred at reflux under N₂ for18 hours. The cooled reaction was poured into H₂O and the aqueousmixture was extracted with EtOAc. The EtOAc extract was washed 2 timeswith H₂O, 2 times with brine and after drying with MgSO₄ the solvent wasremoved in vacuo to yield 5.1 g of a dark oil. The oil was purified bypreparative HPLC (Water's Associates Prep LC/System 500, using 2 silicagel columns and 4% MeOH—CH₂Cl₂ as eluent) to afford 2.65 g (65%) of abeige solid. Recrystallization from ethanol gave 2.2 g (54%) of a beigepowder, m.p.=118°-121° C.

ANALYSIS: Calculated for C₂₃H₂₄FN₃O₂: 70.21% C; 6.15% H; 10.68% N;Found: 69.80% C; 6.21% H; 10.78% N

EXAMPLE 1416-Fluoro-3-[1-[3-[(isoquinol-5-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolesesquifumarate

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8g, 13 mmol), 5-(3-chloropropoxy)isoquinoline (2.8 g, 13 mmol), K₂CO₃(1.7 g) and CH₃CN (50 ml) was refluxed for 16 hours. The reaction wasfiltered and the filtrate was concentrated to an oil. The filter cakewas treated with H₂O, and the aqueous suspension was extracted withCH₂Cl₂. The filtrate was also extracted with CH₂Cl₂, and the extractswere combined, washed (H₂O), dried (K₂CO₃) and concentrated to yield 5.4g of a brown oil. The oil was purified by HPLC on silica gel columns,eluting with CH₂Cl₂/MeOH (5%), to afford 2.3 g of a yellow oil. The oilwas dissolved in EtOAc and fumaric acid (0.66 g, 1 eq) was added. Themixture was refluxed briefly, and then stirred at ambient temperaturefor 16 hours. The resulting white solid was collected to afford 2.2 g ofthe fumarate salt. The compound was recrystallized from DMF to yield 1.4g (18.6%) of the isoquinoline as a sesquifumarate, m.p.=213°-215° C.

ANALYSIS: Calculated for C₃₀H₃₀FN₃O₈: 62.17% C; 5.22% H; 7.25% N; Found:62.01% C; 5.11% H; 7.28% N

EXAMPLE 1426-Fluoro-3-[1-[3-[(1-H-indol-4-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 16mmol), K₂CO₃ (2.2 g, 16 mmol), KI (200 mg), 4-(3-chloropropoxy)indole(3.0 g, 14 mmol) and CH₃CN (100 ml) was stirred at reflux under N₂ for 7hours and then at ambient temperature for 68 hours. Reflux was resumedfor an additional 6 hours whereupon a TLC revealed incomplete reaction.K₂CO₃ (0.5 g, 4 mmol) was added and the reaction was stirred at refluxfor 17 hours. The cooled reaction was poured into H₂O and the aqueousmixture was extracted with EtOAc. The organic extract was washed withH₂O and saturated NaCl and after drying over MgSO₄ the solvent wasremoved to afford 5.7 g of a beige solid. The product was purified bypreparative HPLC (Water's Associates Prep LC/System 500 using 2 silicagel columns and 4% MeOH—CH₂Cl₂ as eluent) to yield 3.4 g (61%) of abeige solid. Two consecutive recrystallizations from EtOH provided 2.3 g(41%) of a white powder, m.p.=129°-131° C.

ANALYSIS: Calculated for C₂₃H₂₄FN₃O₂: 70.21% C; 6.15% H; 10.68% N;Found: 69.90% C; 6.15% H; 10.65% N

EXAMPLE 1436-Fluoro-3-[1-[3-[(6-methoxy-1H-indol-5-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehemifumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 14mmol), 5-(3-chloropropoxy)-6-methoxyindole (3.0 g, 13 mmol), K₂CO₃ (2.1g, 14 mmol), KI (200 mg) and CH₃CN (150 ml) was stirred at reflux underN₂ for 48 hours. The cooled reaction was poured into H₂O and the aqueousmixture was extracted with EtOAc. The EtOAc extract was washed with H₂Oand brine and was dried with MgSO₄. Removal of the solvent in vacuo gave5.6 g of a dark oil. The oil was purified by preparative HPLC (Water'sAssociates Prep LC/System 500 using 2 silica gel columns and 2%Et₂NH-EtOAC as eluent) to yield 2.5 g (47%) of a beige solid.Recrystallization from EtOH afforded 2.0 g of and off white powder. A1.8 g (4 mmol) sample was dissolved in warm EtOAc and fumaric acid (0.5g, 4 mmol) was added. The reaction was stirred at ca 40° C. for 30minutes and was then allowed to gradually cool to ambient temperature.The resultant hemifumarate salt was collected and dried to yield 2.0 g.The product was recrystallized from EtOH to provide 1.5 g (25%) of alight beige powder m.p.=186°-188° C.

ANALYSIS: Calculated for C₂₆H₂₈FN₃O₅: 64.84% C; 5.87% H; 8.73% N; Found:64.22% C; 5.85% H; 8.55% N

EXAMPLE 1441-[4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (2.4 g, 10.1mmol), 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (2.5 g, 11.1mmol), NaHCO₃, (0.94 g, 11.1 mmol), KI (100 mg) and CH₃CN (100 ml) wasstirred at reflux under N₂ for 65 hours. The cooled reaction was pouredinto H₂O and the aqueous mixture was extracted with EtOAc. The EtOAcextract was washed with H₂O (1×) and brine (3×) and after drying withMgSO₄ the solvent was evaporated to give 4.2 g of a dark solid. Threeconsecutive recrystallizations from EtOH provided 2.1 g (48%) ofglittery beige crystals m.p.=135°-137° C.

ANALYSIS: Calculated for C₂₃ H₂₅FN₂O₃S: 64.47% C; 5.88% H; 6.54% N;Found: 64.44% C; 5.69% H; 6.29% N

EXAMPLE 1454-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α-methylbenzenemethanol

To a stirred solution of1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone(4.1 g, 9.3 mmol) in 60 ml MeOH-THF (1:1) under N₂ at ambienttemperature, NaBH₄ (0.386 g, 10.2 mmol) was added portionwise. Aftercomplete addition, the reaction was stirred for 3.5 hours and wasconcentrated to yield a white gum. This was triturated with H₂O (2×) andthe aqueous fraction was decanted away. Residual water was removed underhigh vacuum to afford 5.0 g of a white powder. The compound was taken upin boiling toluene and the insolubles were filtered away. Concentrationof the toluene filtrate afforded 3.8 g of a beige solid. Purificationvia preparative HPLC (Water's Associates prep LC/System 500, using 2silica gel columns and 2% Et₂NH-EtOAc) provided 2.7 g of a light beigesolid. The product was recrystallized from EtOAc to afford 1.7 g (42%)of a pure white powder, m.p.=113°-115° C.

ANALYSIS: Calculated for C₂₄H₂₉FN₂O₃S: 64.84% C; 6.58% H; 6.30% N;Found: 64.85% C; 6.44% H; 6.19% N

EXAMPLE 146(R)-(−)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propylacetate fumarate

To a mixture of(R)-(−)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanol(3.2 g, 11 mmol), triethylamine (3.2 g, 11 mmol) in DCM (100 ml), acetylchloride (890 mg, 11.3 mmol) was added dropwise at 0° C. The mixture wasstirred at room temperature for 4.5 hours. The solvent was removed on arotary evaporator. The triethylamine HCl salt was filtered off using asmall amount of DCM. The crude product was dissolved in DCM was purifiedby flash chromatography over a silica gel column (SiO₂, 30 g; elutedwith DCM and 1% CH₃OH in DCM). The oil, thus purified, weighed 2.11 g(58%). This oil was treated with a solution of fumaric acid (695 mg, 1.0eq.) in ethanol to give the fumarate salt. Recrystallization fromethanol and isopropyl ether again yielded white crystals, 2.09 g,m.p.=118°-120° C.

ANALYSIS: Calculated for C₁₈H₂₃FN₂O₃•C₄H₄O₄: 58.66% C; 6.04% H; 6.22% N;Found: 58.53% C; 5.76% H; 8.91% N

EXAMPLE 1471-(R)-(−)-[4-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propoxy]-3-methoxyphenyl]ethanonefumarate (A) (R)-(−)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperdinyl]-2-methyl-1-propyl methanesulfonate

To a mixture of(R)-(−)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperdinyl]-2-methyl-1-propanol(7.26 g, 24.8 mmol), triethylamine (3 ml, 30 mmol) in methylene chloride(DCM, 120 ml), methanesulfonyl chloride (3.13 g, 27.3 mmol) was addeddropwise at 0° C. The mixture was stirred at room temperature for 1hour., then concentrated down to a crude mixture. Triethylaminehydrochloride salt was removed by filtration with DCM/ether as solvent.The crude oily mixture was purified with a flash chromatography column(SiO₂, 90 g; eluted with DCM). The colorless oil, which is themethanesulfonate ester, weighed 6.48 g (70%), and was used directly inthe following step.

(B)1-(R)-(−)-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylproproxyl-3-methoxyphenyl]ethanonefumarate

A solution of the above methansulfonate (6.48 g, 175 mmol) in DMF (5 ml)was added in one portion to an aged (hour) cold mixture ofacetovanillone (4.13 g, 24.9 mmol) and sodium hydride (670 mg, 26.5mmol) in DMF (40 ml) at 0° C. The resulting mixture was warmed to ˜50°C. briefly and stirred at room temperature for 16 hours. The mixture wasextracted into DCM (500 ml) and washed twice with water, then brine. Theorganic solution was dried over MgSO₄ and concentrated to an oil. Thiscrude mixture was purified twice by flash chromatography over a silicagel column. The material thus purified weighed 5.37 g. The fumarate saltwas prepared by treatment of purified oil with fumaric acid (1.0 eq.) inethanol and ether. Slightly off-white crystals were collected: 3.76 g(38%), m.p.=141°-142° C.

ANALYSIS: Calculated for C₂₅H₂₉FN₂O₄•C₄H₄O₄: 62.58% C; 5.98% H; 5.03% N;Found: 62.52% C; 5.75% H; 4.96% N

EXAMPLE 1483-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2,2-dimethyl-1-propanolfumarate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6mmol), K₂CO₃ (12.5 g, 17.5 mmol), 3-bromo-2,2-dimethyl-1-propanol (3 g,21 mmol, 1.5 eq.), tetra-butylammonium hydrogen sulfate (1 g, phasetransfer catalyst) in water (5 ml) and acetonitrile (150 ml) was heatedat reflux for 43 days. TLC showed a small spot for the expected product.The mixture was diluted with EtOAc (400 ml) and washed with brine. Theorganic solution was dried and concentrated to a dark brown mixture. Thecrude mixture was purified carefully by flash chromatography (SiO₂, 95 gto afford the dried pure product; 260 mg, (6%) as an oil. This oil wasconverted to the fumarate salt by treatment with fumaric acid (98.5 mg,1.0 eq.) in ethanol. Recrystallization from ethanol:ether yielded 210 mgof white crystals, m.p.=144°-145° C.

ANALYSIS: Calculated for C₁₇H₂₃FN₂O₂•C₄H₄O₄: 59.70% C; 6.44% H; 6.63% N;Found: 59.52% C; 6.38% H; 6.52% N

EXAMPLE 1491-(S)-(+)-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propoxy]-3-methoxyphenyl]ethanonefumarate (A)(S)-(+)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propylmethanesulfonate

To a mixture of(S)-(+)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanol(8.8 g, 30 mmol), triethylamine (3.2 g, 32 mmol) in dichloromethane(DCM, 150 ml), methanesulfonyl chloride (4 g, 35 mmol) was addeddropwise at 0° C. over 10 minutes. The mixture was stirred at roomtemperature for 1 hour, then concentrated. Triethylamine HCl salt wasfiltered off with a little DCM as solvent. The crude oil was purifiedwith a flash chromatography column (SiO₂, 90 g; eluted with DCM). Thecolorless oil thus purified weighed 5.28 g (47%) was used immediately inthe following step.

(B)1-(S)-(+)-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-propoxyl]-3-methoxyphenyl]ethanonefumarate

A solution of(S)-(+)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propylmethanesulfonate (5.28 g, 14.27 mmol) in dimethylformamide (DMF, 10 ml)was added in one portion to an aged (1 hour) cold mixture ofacetovanillone (3.55 g, 33.1 mmol) and sodium hydride (530 mg, 22 mmol)in DMF (35 ml) at 0° C. under N₂. The reaction was stirred overnight (16hours.) at room temperature. The mixture was diluted with EtOAc andwashed with H₂O (2 times) and brine. The organic solution was dried andconcentrated to an oil (9.4 g). The crude oil mixture was purified byflash chromatography (SiO₂, 60 g). The oil thus purified weighed 4.3 g,(68%) and was converted to the fumarate salt (fumaric acid, 1.13 g) inethanol. Recrystallization from ethanol gave 1.36 g of white crystals,m.p.=163°-165° C.

ANALYSIS: Calculated for C₂₅H₂₉FN₂O₄•C₄H₄O₄: 62.58% C; 5.98% H; 5.03% N;Found: 62.40% C; 5.84% H; 4.92% N

EXAMPLE 150 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylthioacetate fumarate

To a stirred solution of 0° C. of triphenlyphsphine (13.3 g, 50 mmol) inTHF (150 ml), diisopropylazodicarboxylate (10.2 ml, 50 mmol) was addeddropwise. After stirring at 0° C. for 0.5 hour, a solution of6-fluoro-3-[1-(2-hydroxyethyl)-4-piperidinyl]-1,2-benzisoxazole (8.5 g,32 mmol) and thioacetic acid (10.2 ml, 0.14 mol) in DMF (35 ml) wasadded dropwise. The reaction was then stirred at ambient temperature for16 h, and then it was concentrated at 60 C, under vacuum, to yield a redoil. The oil was triturated with H₂O, and then it was flashchromatographed on silica gel, eluting first with CH₂Cl₂ and then with10% MeOH—CH₂Cl₂. The appropriate fractions were concentrated to yield16.5 g of an oil. The oil was triturated with Et₂O and the solid(reaction by-products) that formed was removed by filtration. Thefiltrate was treated with fumaric acid (4.3 g), and 7.2 g of thefumarate salt of the desired product was obtained as an off white solid.The salt was recrystallized from EtOAc and then twice from EtOH toafford 1.0 g (7.0%) of the thioacetate as an off white solid,m.p.=118°-120° C.

EXAMPLE 151N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4,5-dichlorophthalimide

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.83g, 10.7 mmol) and 4,5-dichlorophthalic anhydride (2.56 g, 11.93 mmol,1.1 eq) in methylene chloride (100 ml, DCM) was stirred for 2 h, whilesolids precipitated and the TLC showed disappearance of the startingmaterial. The solvent was removed, and the crude solid was loaded onto aflash chromatography column (28 g, SiO₂, sorbsil C-30, eluted with 1%MeOH in DCM; 0.5% of NH₄OH was added towards the end of elution). Thematerial thus purified weighed 2.26 g as white crystals.Recrystallization twice from a large volume of hot ethanol (400 ml)yielded 1.57 g of white shining crystals, m.p.=132°-134° C.

ANALYSIS: Calculated for C₂₂H₁₈Cl₂FN₃O₃: 57.16% C; 3.92% H; 9.09% N;Found: 57.13% C; 3.63% H; 8.93% N

EXAMPLE 152N-[2-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimidehydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (3.3 g, 14mmol), 2-bromoethylphthalimide (3.7 g, 14.7 mmol), K₂CO₃ (2.0 g) andCH₃CN (85 ml) was stirred and refluxed for 2.5 hours. The reaction waspoured into H₂O and a white precipitate resulted, which was collected toafford 2.0 g of product. The aqueous filtrate was extracted with CHCl₃,the extract washed (H₂O), dried (MgSO₄) and was concentrated to afford3.5 g of an off-white solid. Upon trituration of this solid withacetone, an additional 2.0 g of product was realized. The two sampleswere combined and suspended in MeOH (50 ml), and ethereal HCl was addeduntil the reaction mixture was acidic. After stirring for 1 hour atambient temperature, Et₂O (50 ml) was added to afford 3.7 g of thehydrochloride salt. The salt was recrystallized from MeOH-Et₂O to yield2.3 g (37%) of the compound as a white solid, m.p.=271°-273° C.

ANALYSIS: Calculated for C₂₂H₂₀FN₃O₂S•HCl: 59.25% C; 4.75% H; 9.42% N;Found: 58.99% C; 4.60% H; 9.33% N

EXAMPLE 153N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]ethyl]-3,6-dichlorophthalimide

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.44g, 9.24 mmol) and 3,6-dichlorophthalic anhydride (2.01 g; 9.27 mmol) indichloromethane (DCM, 50 ml) was stirred at room temperature for 1 hour.White precipitates formed and the TLC of the reaction mixture showedthat there was no starting amine remaining. The solvent was strippeddown and the white solids which were poorly soluble in DCM were loadedonto a flash chromatography column, (SiO₂, 30 g) and the column waseluted with a solution of 1% C;H₃OH in DCM. The desired product thusobtained weighed 2.29 g (54%). Recrystallization from hot ethanolyielded 2.15 g of white crystals, m.p.=163°-164° C.

ANALYSIS: Calculated for C₂₂H₁₈Cl₂FN₃O₃: 57.16% C; 3.92% H; 9.09% N;Found: 57.16% C; 3.64% H; 9.13% N

EXAMPLE 154N-2-[4-(6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]ethyl]-4-chlorophthalimide

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.13g, 8.07 mmol), 4-chlorophthalic acid monosodium salt (2.2 g, 10 mmol)and dicyclohexylcarbodiimide (DCC, 4.25 g, 20.6 mmol) in acetonitrile(150 ml) was stirred at room temperature for 24 hours. The cloudymixture was filtered, then the solvent was stripped down. The residuewas partitioned between water and dichloromethane (DCM). The DCMsolution was washed with brine and dried over MgSO₄. The solvent wasremoved. The crude product was purified on a flash chromatography column(SiO2, 35 g; eluted with DCM, and 1% C;H₃OH in DCM). The desired productthus obtained weighed 1.3 g. Recrystallization from ethanol yielded 590mg as white crystals, m.p.=170°-171° C.

ANALYSIS: Calculated for C₂₂H₁₉FN₃O₃: 61.76% C; 4.48% H; 9.82% N; Found:61.87% C; 4.39% H; 9.89% N

EXAMPLE 155N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-fluorophthalimide

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.37g, 8.98 mmol), 3-fluorophthalic acid (1.82 g, 9.9 mmol) anddicyclohexylcarbodiimide (DCC, 5.5 g, 26.7 mmol, 2.6 eq) indichloromethane (DCM, 250 ml) was stirred at room temperature for 18hours. The solids were filtered off. The organic solution wasconcentrated down. The residue was purified on a flash chromatographycolumn (SiO₂, 50 g; eluted with 1.4 liter; 2-6% C;H₃OH:DCM, 1 liter).The desired product thus obtained weighed 2.64 g (71%) as an off-whitesolid. Recrystallization from hot ethanol gave 1.41 g of white crystals,m.p.=142°-143° C.

ANALYSIS: Calculated for C₂₂H₁₉F₂N₃O₃: 64.22% C; 4.66% H; 10.21% N;Found: 64.11% C; 4.70% H; 10.14% N

EXAMPLE 156N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]ethyl]-4-fluorophthalimide

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (3.2 g,12 mmol), 4-fluorophthalic anhydride (freshly prepared according to theprocedure of Markezich, U.S. Pat. No. 3,956,321, 1976; 2.0 g, 12 mmol)and dicyclohexylcarbodiimide (DCC, 2.48 g, 12 mmol) in chloroform (100ml) was stirred at room temperature for 18 hours. The insolubles werefiltered off. The solution was loaded onto a flash chromatography column(SiO₂, 45 g) then was eluted with a solution of 2% methanol in methylenechloride. The fractions containing the desired product were pooled andconcentrated to yield 2.9 g of white solid. The material was convertedto a hydrochloride salt by treatment with a solution of hydrochloride inethanol. Recrystallization from ethanol gave the pure sample, 1.01 g,m.p. 253°-255° C.

ANALYSIS: Calculated for C₂₂H₁₉FN₃O₃.HCl: 59.00% C; 4.50% H; 9.38% N;Found: 58.81% C; 4.38% H; 9.48% N

EXAMPLE 157N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]ethyl]-4-methylphthalimide

A mixture of2-[4-([6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.44g, 9.24 mmol), 4-methylphthalic anhydride (1.76 g, 10.8 mmol) anddicyclohexylcarbodiimide (2.1 g, 1.0 mmol) in dichloromethane (DCM, 100ml) was stirred at room temperature for 2 hours. The insolubles werefiltered off. The DCM solution was concentrated to a crude solid. Thiswas purified on a flash chromatography column (35 g, SiO₂, Sorbsil-C-30;eluted with 1% C;H₃OH in 99% DCM). The material thus purified weighed1.0 g (26%) as a white solid. Recrystallization from hot ethanol gave665 mg of crystals, m.p.=138°-140° C.

ANALYSIS: Calculated for C₂₃H₂₂FN₃O₃: 67.80% C; 5.44% H; 10.31% N;Found: 67.67% C; 5.48% H; 10.30% N

EXAMPLE 158N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-methoxyphalimide

A stirred mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.63g, 10 mmol) and 4-methoxyphthalic anhydride (1.78 g, 10 mmol) indichloromethane (100 ml) is stirred at room temperature for 3 hours. Thesolvent is then removed under reduced pressure and the residual materialis purified by flash chromatography. The product is purified further byrecrystallization to giveN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-methoxy-phthalimide.

EXAMPLE 159N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-nitrophthalimidehydrochloride

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.9 g,11 mmol), 4-nitrophthalic anhydride (2.33 g, 12.1 mmol) anddicyclohexylcarbodiimide (2.25 g, 11 mmol) in dichloromethane (DCM, 150ml) was stirred at room temperature for 16 hours. The mixture wasfiltered. The brownish solution was loaded onto a flash chromatographycolumn, (SiO₂, 35 g; eluted with DCM, then 2% C;H₃OH in DCM). Thedesired product thus obtained weighed 2.35 g (49%) as a pale whitesolid, m.p. 191°-193° C. This solid was converted to the hydrochloridesalt by treatment with an HCl solution in ethanol to yield 1.54 g,m.p.=250°-253° C. dec.

ANALYSIS: Calculated for C₂₂H₁₉FN₄O₅.HCl 55.64% C; 4.25% H; 11.90% N;Found: 55.81% C; 4.08% H; 11.67% N

EXAMPLE 1604-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-2-hydroxybutanefumarate

To a solution of ethyl3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (3.21 g,10 mmol) in tetrahydrofuran (THF, 100 ml), was added methylmagnesiumbromide (10 ml, 30 mmol, 3M solution in ether) dropwise over minutes atroom temperature under N₂. The resulting mixture was stirred for 16hours. The mixture was slowly hydrolyzed with aqueous NH₄Cl solution.The THF solution was diluted with EtOAc (300 ml), then was washed withwater and brine. The organic solution was separated and dried overMgSO₄. After removal of solvent, the crude product was purified by flashchromatography (25 g, SiO₂; eluted with 1 CH₃OH:99 DCM). The materialthus purified weighed 2.36 g (77%) as white crystals. This was convertedto the fumarate salt by treatment with fumaric acid (895 mg) in ethanol.Recrystallization from ethanol yielded white crystals, 2.47 g,m.p.=156°-158° C.

ANALYSIS: Calculated for C₁₇H₂₃FN₂O₂.C₄H₄O₄: 59.70% C; 6.44% H; 6.63% N;Found: 59.40% C; 6.27% H; 6.28% N

EXAMPLE 161 Ethyl3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate fumarate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7mmol), K₂CO₃ (3.8 g, 27.5 mmol) and ethyl bromopropionate (5 g, 27.6mmol, 1.2 eq) in acetonitrile (200 ml) was heated at reflux for 16hours. The mixture was cooled and filtered. The solvent was removed, andthe residue was purified on a flash chromatography column (60 g, SiO₂,eluted with DCM). The material thus purified weighed 7.27 g (83%). Thefumarate salt was prepared by treatment of the free base (2.17 g) withfumaric acid (820 mg, 1.0 eq) in ethanol. Recrystallization from ethanolyielded 2.49 g of white crystals, m.p.=135°-136° C.

ANALYSIS: Calculated for C₁₇H₂₁FN₂O₃.C₄H₄O₄: 57.79% C; 5.77% H; 6.42% N;Found: 57.86% C; 5.67% H; 6.30% N

EXAMPLE 1622,3-dihydro-2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-hydroxy-1H-isoindol-1-one

To a suspension ofN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide(7.8 g, 19.8 mmol) in methanol (250 ml) and DCM (30 ml) was added NaBH₄(1.7 g, 45.5 mmol) at room temperature under nitrogen. After stirringfor 0.5 hours the homogeneous reaction mixture was concentrated. Theremaining solid was purified on a flash chromatography column (SiO₂, 1:1EtOAc/DCM, increased to 10% MeOH) to give 7.0 g (90%) of the desiredproduct as a solid which was recrystallized from EtOAc, m.p.=172°-173°C.

ANALYSIS: Calculated for C₂₂H₂₂FN₃O₃: 66.82% C; 5.61% H; 10.63% N;Found: 66.63% C; 5.52% H; 10.51% N

EXAMPLE 1632,3-dihydro-2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1H-isoindol-1-one

To2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-one(2.2 g, 5.6 mmol) was added a solution of trifluoroacetic acid (11.0 ml)in dichloromethane (30 ml) at room temperature, under nitrogen.Triethylsilane (1.5 ml) was then added and the reaction mixture wasallowed to stir for 18 hours at which time it was poured into a NaHCO₃(sat.). The layers were separated and the aqueous phase was extractedwith DCM (3×). The combined organics were washed with brine and dried(Na₂SO₄). Filtration and concentration gave the crude product as a solidwhich was recrystallized from EtOAc, to give 1.6 g (79%) of the desiredproduct as a white solid, m.p.=166°-168° C.

ANALYSIS: Calculated for C₂₂H₂₂FN₃O₂: 69.64% C; 5.84% H; 11.07% N;Found: 69.37% C; 5.70% H; 11.00% N

EXAMPLE 164(S)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropyl-methylcarbamate

To a solution of2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-one(3.1 g, 10.6 mmol) in dry THF (120 ml) was added methyl isocyanate (0.66ml, 11.1 mmol) followed by milled K₂CO₃ (2.2 g, 15.9 mmol) at roomtemperature, under nitrogen. The reaction mixture was stirred for 3 daysat which time it was filtered through a pad of Celite and the solidswashed with EtOAc. The combined filtrates were concentrated to give thecrude product which was purified via flash column chromatography (silicagel, 2% Et₃N/EtOAc). The product containing fractions were concentratedto give 2.7 g (73%) of the desired product as an oil which solidified onstanding. Recrystallization from EtOAc/pet.ether gave the product as asolid, m.p.=72°-74° C.

ANALYSIS: Calculated for C₁₈H₂₄FN₃O₃: 61.88% C; 6.92% H; 12.03% N;Found: 61.82% C; 7.02% H; 11.77% N

EXAMPLE 165(S)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropyldecanoate fumarate

To a solution of2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-one(3.2 g, 10.9 mmol) in DCM (110 ml) was added decanoyl chloride (2.3 ml,10.9 mmol) at 0° C., under nitrogen. The reaction mixture was stirredfor 1.25 hours (0° C.) at which time it was poured into NaHCO₃ (sat.).The layers were separated and the aqueous phase was extracted with DCM(2×). The combined organics were dried, filtered and concentrated togive the crude product which was purified via flash columnchromatography (silica gel, 30% EtOAc/DCM). The product containingfractions were concentrated to give 3.4 g (70%) of the desired productas a yellow oil. The fumarate salt was prepared in ethanol with fumaricacid (1.05 eq.). The white salt was filtered and washed with isopropylether, m.p. 110°-112° C.

ANALYSIS: Calculated for C₂₆H₃₉FN₂O₃.C₄H₄O₄: 64.04% C; 7.70% H; 4.98% N;Found: 64.07% C; 7.75% H; 4.90% N

EXAMPLE 166(S)-6-Fluoro-3-[1-(3-methoxyphenyl-2-methylpropyl)-4-piperidinyl]-1,2-benzisoxazole

To a solution of2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-one(3.3 g, 11.3 mmol) in dry THF (120 ml) was added potassium tert-butoxide(1.9 g, 16.9 mmol) followed by dimethyl sulfate (1.2 ml, 11.9 mmol) atroom temperature, under nitrogen. The reaction mixture was stirred for21 hours at which time it was filtered through a pad of Celite and thesolids washed with EtOAc. The combined filtrates were concentrated togive the crude product. Purification via flash column chromatography(silica gel, 0-20% acetone/DCM) afforded 1.6 g (46%) of the desiredproduct as a solid, m.p.=40°-42° C.

ANALYSIS: Calculated for C₁₇H₂₃FN₂O₂: 66.65% C; 7.57% H; 9.14% N; Found:66.49% C; 7.48% H; 9.12% N

EXAMPLE 167(+)-6-Fluoro-3-[1-(3-hydroxybutyl)-4-piperidinyl]-1,2-benzisoxazole

Racemic 3-hydroxybutyl tosylate was prepared in a manner described byFerreira et al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solutionof the racemic tosylate (9.2 g, 37.7 mmol) in acetonitrile (190 ml) wasadded 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (8.3 g, 37.7 mmol)followed by milled potassium carbonate (7.8 g, 56.6 mmol) at roomtemperature under nitrogen. The reaction mixture was warmed to refluxfor 4.5 hours and allowed to cool to room temperature. The solids wereremoved via filtration through a pad of Celite and were washed withEtOAc. The combined filtrates were concentrated to give the crudeproduct. Purification via preparative HPLC (silica gel, 10% MeOH/EtOAc)afforded 6.3 g (57%), m.p.=100°-102° C.

ANALYSIS: Calculated for C₁₆H₂₁FN₂O₂: 65.73% C; 7.24% H; 9.58% N; Found:65.59% C; 7.30% H; 9.52% N

EXAMPLE 168(S)-6-Fluoro-3-[1-(3-hydroxy-2-methylpropyl)-4-piperidinyl]-1,2-benzisothiazolefumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.6 g, 20mmol), (R)-(−)-3-bromo-2-methyl-1-propanol (3.0 g, 20 mmol), K₂CO₃ (2.7g, 20 mmol), tetrabutylammonium sulfate (0.058 g), CH₃CN (95 ml) and H₂O(19 ml) was stirred and refluxed for 4.5 hours. After standing atambient temperature for 16 hours, the reaction was poured into H₂O, andsubsequent extractive workup of the aqueous with EtOAc yielded 6.8 g ofa partially solidified oil. The product was purified by flashchromatography on silica gel, eluting the column with CH₂Cl₂, then 2%MeOH—CH₂Cl₂ and finally 5MeOH—CH₂Cl₂. Concentration of the appropriatefractions yielded 5.2 g of a waxy solid. The solid was dissolved inacetone and fumaric acid (1.9 g, 1.0 eq) was added and the reactionbriefly heated at reflux. The resultant fumarate salt precipitated fromsolution yielding 4.8 g of white solid. The compound was recrystallizedfrom acetonitrile to yield 3.1 g (36%) of the alcohol as a white solid,m.p.=151°-153° C.

ANALYSIS: Calculated for C₁₆H₂₁FN₂OS.C₄H₄O₄: 56.59% C; 5.94% H; 6.60% N;Found: 56.31% C; 5.96% H; 6.48% N

EXAMPLE 169N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]ethyl]-3,6-difluorophthalimide

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (1.53g, 5.8 mmol), 3,6-difluorophthalic anhydride (1.0 g, 5.43 mmol) anddicyclohexylcarbodiimide (DCC, 1.84 g, 8.9 mmol) in methylene chloride(DCM, 100 ml) was stirred for 6 hours, and then left standing overnightat room temperature. The solids were filtered off. The solution wasloaded onto a silica gel column (35 g, Sorbsil C-30), then eluted with amixture of methanol and DCM (1%-2%). The fractions containing thedesired product were pooled and concentrated to give 1.23 g of whitesolid. Recrystallization from DCM and hot ethanol yielded 1.03 g (44.5%)of white crystals, m.p.=144°-145° C.

ANALYSIS: Calculated for C₂₂H₁₈F₃N₃O₃: 61.54% C; 4.23% H; 9.79% N;Found: 61.63% C; 3.83% H; 9.77% N

EXAMPLE 170N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,2,3,4-tetrahydro-isoquinoline-1,3,-dione

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.45g, 9.28 mmol), 1;1omophthalic anhydride (1.78 g, 10.9 mmol) and DCC (2.2g, 10.7 mmol) in CHCl₃ (100 ml) was stirred at room temperature for 3.5hours. The insolubles were filtered off. The solution was loaded onto aflash chromatography column (Sorbsil C-30, 40 g), eluted with DCM (1.5l), 2% C;H₃OH in DCM (1 l), then washed with 20% C;H₃OH in DCM. Thefractions containing the front spot were pooled and concentrated to give500 mg of yellow solid. This solid was recrystallized again from ethanolto provide 340 mg (10.7%) of crystals, m.p.=148°-150° C.

ANALYSIS: Calculated for C₂₂H₂₂FN₃O₃: 67.80% C; 5.44% H; 10.31% N;Found: 67.54% C; 5.31% H; 10.17% N

EXAMPLE 1712-[4-[(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethylaminesesquifumarate

To a stirred solution ofN-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimide(17.0 g, 42 mmol) and MeOH (200 ml) under N₂ was added, dropwise,hydrazine monohydrate (4.2 g, 83 mmol). After complete addition, thereaction was stirred at reflux for 17 hours. The reaction mixture wasconcentrated and the resultant residue was dissolved in H₂O. The aqueoussolution was acidified to pH˜2 with concentrated HCl and the precipitatewas filtered. The filtrate was basified with 50% N;aOH and the productwas extracted into CH₂Cl₂. The CH₂Cl₂ extract was washed with H₂O, driedwith MgSO₄ and concentrated to yield 6.0 g (52%) of a beige oil. A 5.8 gsample of the oil (21 mmol) was warmed in EtOH (100 ml) and fumaric acid(2.7 g, 23 mmol) was added. The solution was refluxed gently for 15minutes and was stirred at ambient temperature for 1.5 hours. AnhydrousEt20 (400 ml) was added and the product collected to yield 7.1 g of anoff-white powder. A portion (3.0 g) was recrystallized from MeOH-Et₂O toprovide 1.7 g (22%) of the sesquifumarate salt as a white powderm.p.=169°-171° C.

ANALYSIS: Calculated for C₁₄H₁₈FN₃S.1.5C₄H₄O₄: 52.97% C; 5.35% H; 9.27%N; Found: 52.96% C; 5.44% H; 9.39% N

EXAMPLE 172(S)-6-Fluoro-3-[1-(3-hydroxybutyl)4-piperidinyl]-1,2-benzisoxazole

(S)-Hydroxybutyl tosylate was prepared in a manner described by Ferreiraet al., Tetrahedron, b 46, pp. 6311-6318, (1990). To a solution of thetosylate (6.8 g, 28.0 mmol) in acetonitrile (150 ml) was added6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (6.2 g, 28.0 mmol) followedby milled potassium carbonate (5.8 g, 42.0 mmol) at room temperatureunder nitrogen. The reaction mixture was warmed to reflux for 3 hoursand allowed to cool to room temperature. The solids were removed viafiltration through a pad of Celite and were washed with EtOAc. Thecombined filtrates were concentrated to give the crude product.Purification via flash column chromatography (silica gel, 0-10%MeOH/EtOAc) afforded 5.5 g (67%) of the desired product as an oil whichsolidified on standing, m.p.=84°-86° C.

ANALYSIS: Calculated for C₁₆H₂₁FN₂O₂: 65.73% C; 7.24% H; 9.58% N; Found:65.58% C; 6.83% H; 9.50% N

EXAMPLE 173(R)-6-Fluoro-3-[1-(3-hydroxybutyl)-4-piperidinyl]-1,2-benzisoxazole

(R)-Hydroxyburyl rosylate was prepared in a manner described by Ferreiraet al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solution of thetosylate (8.4 g, 34.2 mmol) in acetonitrile (120 ml) was added6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (7.5 g, 34.2 mmol) followedby milled potassium carbonate (7.1 g, 51.3 mmol) at room temperatureunder nitrogen. The reaction mixture was warmed to reflux for 2 hoursand allowed to cool to room temperature. The solids were removed viafiltration through a pad of Celite and were washed with EtOAc. Thecombined filtrates were concentrated to give the crude product.Purification via flash column chromatography (silica gel, 10%MeOH/EtOAc) afforded 6.0 g (60%) of the desired product as an oil whichsolidified on standing, m.p.:=82°-84° C.

ANALYSIS: Calculated for C₁₆H₂₁FN₂O₂: 65.73% C; 7.24% H; 9.58% N; Found:65.66% C; 7.13% H; 9.53% N

EXAMPLE 174N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide

A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (4.0 g, 18 mmol),K₂CO₃ (2.7 g, 20 mmole), N-(2-bromoethyl)phthalimide (4.8 g, 19 mmole)and CH₃CN (100 ml) was stirred at reflux under N₂ for 4 hours. Afterstanding at ambient temperature for 65 hours, the reaction was pouredinto H₂O. The resultant solid was collected to yield 4.0 g of a yellowpowder. The product was recrystallized twice from ethanol to yield 3.5 g(50%) of a beige powder m.p.=220°-223° C.

ANALYSIS: Calculated for C₂₁H₂₀FN₅O₂: 64.11% C; 5.12% H; 17.80% N;Found: 64.16% C; 5.04% H; 17.82% N

(A) N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimidehydrochloride

A 5.0 g sample ofN-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide wassuspended in methanol (130 ml) and was made acidic with ethereal-HCl.After stirring for 1 hour, anhydrous ether (100 ml) was added and thesuspension was stirred for an additional 30 minutes. The solid wascollected and dried to afford 4.5 g of an off-white powder. This wascombined with an additional sample (7.3 g total) and recrystallizationfrom MeOH gave 4.3 g of the salt as an off-white powder, mp=265°-268° C.

ANALYSIS: Calculated for C₂₁H₂₀FN₅O₂.HCl: 58.62% C; 4.92% H; 16.29% N;Found: 58.60% C; 4.83% H; 16.19% N

EXAMPLE 175 Ethyl3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propionatehydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (6.0 g, 25mmol), ethyl 3-bromopropionate (4.5 g, 25 mmol), K₂CO₃ (3.5 g) and CH₃CN(100 ml) was stirred and refluxed for 16 hours. The reaction was pouredinto H₂O, and after extractive workup with EtOAc, 6.0 g of an orange oilwas realized. The oil was dissolved in Et₂O and ethereal HCl was addedto precipitate 6.3 g of a white hydrochloride salt. The salt wasrecrystallized from CH₃CN to yield 6.0 g (64%) of the desired compound.An analytical sample was obtained by recrystallization of a 1.0 g samplefrom EtOH-Et₂O to yield 0.8 g of a white solid, m.p.=197°-199° C.

ANALYSIS: Calculated for C₁₇H₂₁FN₂O₂S.HCl: 54.76% C; 5.95% H; 7.51% N;Found: 54.77% C; 5.99% H; 7.28% N

EXAMPLE 1764-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]-2-methyl-2-hydroxybutanehemifumarate

To a stirred solution, under N₂, of ethyl3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propionate (3.1 g,9 mmol), in THF (100 ml) was added, dropwise, methylmagnesium bromide(9.0 ml, 27 mmol of a 3M solution in ether). The reaction was stirred atambient temperature for 16 hours and then a saturated solution NH₄Cl wasadded dropwise, with cooling. The reaction was further diluted with H₂Oand after extractive workup of the aqueous mixture with EtOAc, 2.8 g ofa waxy solid resulted. The solid was dissolved in EtOAc and 3.0 g offumaric acid was added, and 5.0 g of a fumarate salt was collected,which was contaminated with unreacted fumaric acid. The crude salt wasrecrystallized from MeOH-Et₂O, and then from DMF to afford 1.6 g (45.7%)of the desired compound as a hemifumarate, m.p.=237°-239° C.

ANALYSIS: Calculated for C₁₇H₂₃FN₂OS.C₄H₄O₄: 59.98% C; 6.64% H; 7.36% N;Found: 59.75% C; 6.65% H; 7.39% N

EXAMPLE 177N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-hydroxyphthalimidehydrochloride

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.48g, 9.3 mmol), 3-hydroxyphthalic anhydride (1.8 g, 10.9 mmol) anddicyclohexylcarbodiimide (2.2 g, 10.7 mmol) in chloroform (100 ml) wasstirred at room temperature for 48 hours. The mixture was filtered. Theyellow solution was loaded onto a flash chromatography column (SiO₂, 40g; eluted with DCM, 1 l; and 2% C;H₃OH in DCM, 1 l). The desired productthus obtained as a light yellow solid weighed 2.12 g (55%),m.p.=156°-157° C. This material was converted to the hydrochloride saltby treatment with a solution of hydrochloric acid in ethanol. Theoff-white crystals were collected: 1.97 g, m.p.:=270°-272° C. dec.

ANALYSIS: Calculated for C₂₂H₂₀FN₃O₄.HCl: 59.26% C; 4.75% H; 9.42% N;Found: 59.34% C; 4.70% H; 9.19% N

EXAMPLE 178N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-fluorophthalimide

A solution of2-[4-[(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]amine (2.7g, 10 mmol), 4-fluorophthalic anhydride (1.6 g, 10 mmol) and DMF (50 ml)was stirred under N₂ at ambient temperature for 1 hour and then at 70°for 2 hours. Most of the DMF was removed in vacuo to afford 4.6 g of adamp, beige solid. The compound was dissolved in anhydrous Et₂O (100 ml)and MeOH (75 ml) and the insolubles were filtered off. The filtrate wasmade acidic with ethereal HCl to precipitate the HCl salt. Additionalanhydrous Et₂O (500 ml) was added and the salt was collected to give 3.5g of a beige solid. Recrystallization from EtOH provided 2.0 g (44%) ofan off-white powder, m.p.=269°-271° C.

ANALYSIS: Calculated for C₂₂H₁₉F₂N₃O₂S.HCl: 56.96% C; 4.35% H; 9.06% N;Found: 57.33% C; 4.33% H; 9.11% N

EXAMPLE 1796-Fluoro-3-[1-(3-hydroxy-3-ethylpentyl)-4-piperidinyl]-1,2-benzisoxazole

To a solution of ethyl3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (3.9 g,12.0 mmol) in THF (100 ml) was added ethylmagnesium bromide (12.0 ml,36.0 mmol, 3.0M in ether) at room temperature under nitrogen (mildexotherm). The reaction mixture was stirred for 17 hours at which timeit was carefully quenched with NH₄Cl (sat., 20 ml). The precipitatedsalts were dissolved into water (25 ml) and the layers were separated.The aqueous phase was extracted with EtOAc (2×) and the combinedorganics were washed with brine and dried (Na₂SO₄). Filtration andconcentration gave the crude product which was purified via flash columnchromatography (silica gel, 1% MeOH/DCM) to give 2.4 g (61%) of thedesired product as an oil which solidified on standing, m.p.=50°-53° C.

ANALYSIS: Calculated for C₁₉H₂₇FN₂O₂: 68.24% C; 8.14% H; 8.38% N; Found:67.99% C; 8.11% H; 8.48% N

EXAMPLE 180 Decanoic acid2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-oxo-2,3dihydro-1H-isoindol-1-ylester

To a solution of2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-2,3-dihydro-3-hydroxy-1H-isoindol-1-one(1.4 g, 3.5 mmol) in DCM (30 ml) was added Et₃N (1.2 ml, 8.8 mmol)followed by decanoyl chloride at 0 C. under nitrogen. After stirring for1 h in the cooling bath, the solvent was removed using a stream ofnitrogen. The remaining residue was diluted with EtOAc and theprecipitated triethylamine hydrochloride was filtered off. The filtratewas concentrated and the remaining oil was flushed through alumina withether to give 1.6 g (83%) of the desired product as a yellow oil.

ANALYSIS: Calculated for C₃₂H₄₀FN₃O₄: 69.92% C; 7.33% H; 7.64% N; Found:69.70% C; 7.39% H; 7.56% N

EXAMPLE 1816-Chloro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1H-benz[de]isoquinoline-1,3(2H)-dione

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.32g, 8.8 mmol) and 4-chloro-1,8-naphthalic anhydride (2.45 g, 10.5 mmol,1.25 eq) in chloroform (120 ml) was stirred at room temperatureovernight. To the mixture was added 5 ml of methanol and the solutionwas concentrated down to 20 ml. The resulting mixture was loaded onto aflash chromatography column (SiO₂, 50 g; eluted with dichloromethane,DCM, 1 l, and 2% C;H₃OH in DCM, 1 l). The product thus obtained as alight yellow solid weighed 2.61 g. Recrystallization from CH₂Cl₂/ethanolgave 2.5 g of pale white crystals, m.p.=207°-209° C.

ANALYSIS: Calculated for C₂₆H₂₁ClFN₃O₃: 65.34% C; 4.43% H; 8.79% N;Found: 64.87% C; 4.32% H; 8.67% N

EXAMPLE 182N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-tert-butylphthalimidefumarate

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.0 g,7.57 mmol) and 4-(t-butyl)phthalic anhydride (1.62 g, 7.94 mmol) indimethylformamide (DMF, 20 ml) was heated at 135° C. for 3 hours. Thesolvent was removed on a rotary evaporator under vacuum, and furtherdried on a vacuum pump. The residue was purified by flash chromatographyover a silica gel column (SiO₂, 35 g; eluted with DCM, and 1-2% ofmethanol in DCM). The product thus obtained as an oil was trituratedwith isopropyl ether and dried to a waxy solid. This solid was convertedto the fumarate salt by treatment with a solution of fumaric acid (778mg) in ethanol. The crystals were collected and weighed: 3.03 g;m.p.=198°-199° C.

ANALYSIS: Calculated for C₂₆H₂₈FN₃O₃.C₄H₄O₄: 63.71% C; 5.70% H; 7.43% N;Found: 63.46% C; 6.05% H; 7.27% N

EXAMPLE 183N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimidehydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (2.5 g, 11 mmol),2-bromoethylphthalimide (3.0 g, 10 mmol), NaHCO₃ (1.0 g) and DMF (30 ml)was stirred and heated at 60 C. for 2.5 hours. The reaction was pouredinto H₂O, and after extractive workup with EtOAc there remained 4.0 g ofa golden oil. The oil was dissolved in EtOAc and ethereal HCl was addedto yield 1.9 g of the hydrochloride salt as a white solid. The solid wasrecrystallized from MeOH-Et₂O and then from DMF to afford 0.54 g (11%)of the compound as a white solid, m.p.=270°-272° C.

ANALYSIS: Calculated for C₂₂H₂₁FN₄O₂.HCl: 61.61% C; 5.17% H; 13.06% N;Found: 61.50% C; 5.05% H; 12.86% N

EXAMPLE 1842-[2-4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-onehydrochloride

To a stirred solution of theN-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimide(2.5 g, 6 mmol) in MeOH (50 ml)-CH₂Cl₂ (20 ml) was added NaBH₄ (0.8 g,21 mmol). The reaction was stirred at ambient temperature for 2 hours,and then the solvent was evaporated. The residue was diluted with H₂O,and extractive workup of the aqueous with CH₂Cl₂ afforded 2.2 g of abeige solid. The solid was combined with a sample from a prior run, andthe combined sample (3.2 g) was chromatographed on a Waters Prep 500 LC,eluting with EtOAc-Et₂NH (5%). Concentration of the appropriatefractions afforded 2.2 g of a white solid. The solid was dissolved inEtOAc and ethereal HCl was added to yield 2.0 g of a hydrochloride salt.The salt was recrystallized first from EtOH and then from DMF to yield1.2 g (31%) of a white solid, m.p.=210°-212° C.

ANALYSIS: Calculated for C₂₂H₂₂FN₃O₂S.HCl: 58.99% C; 5.81% H; 9.38% N;Found: 58.89% C; 5.23% H; 9.16% N

EXAMPLE 185N-[2-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]-4-methylphthalimidehydrochloride

A mixture of2-[4-[(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]amine (3.4g, 12 mmol), 4-methylphthalic anhydride (2.0 g, 12 mmol) and DMF (75 ml)was stirred at 70° C. under N₂ for 3.5 hours. Most of the DMF wasremoved in vacuo, and the oily residue was diluted with H₂O. EtOAc wasadded to the aqueous mixture and the biphase was filtered through Celiteto remove an insoluble yellow solid. The solid was scraped away from theCelite and was dissolved in CH₂Cl₂. The solution was filtered throughthe original Celite cake, and the CH₂Cl₂ filtrate was washed with H₂O,dried with MgSO₄ and concentrated to yield 0.5 g (10%) of an off-whitesolid. The phases of the EtOAc/H₂O filtrate were separated and theaqueous was further extracted with EtOAc. The EtOAc extract was washedwith H₂O, dried with MgSO₄ and concentrated to afford 3.5 g (69%) of anoff-white solid.

The two samples were combined and recrystallized from EtOH to give 2.2 gof a white powder. The product was dissolved in anhydrous ether (200 ml)and methanol (100 ml) and the solution was made acidic with etherealHCl. After ca. 30 minutes of stirring the salt began to precipitate.Additional anhydrous ether (400 ml) was added over 2 hours and theresultant white solid was collected to yield 2.2 g. Recrystallizationfrom MeOH-ether provided 1.7 g (30%) of a white powder, m.p.=268°-271°C.

ANALYSIS: Calculated for C₂₃H₂₂FN₃O₂S.HCl: 60.06% C; 5.04% H; 9.14% N;Found: 60.01% C; 5.00% H; 9.12% N

EXAMPLE 1866-Fluoro-3-[1-(3-hydroxy-3-propylhexyl)-4-piperidinyl]-1,2-benzisoxazolehydrochloride

To a solution of ethyl3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (4.5 g,14.0 mmol) in THF (120 ml) was added propylmagnesium chloride (21.1 ml,42.0 mmol, 2.0M in ether) at room temperature under nitrogen (mildexotherm). The reaction mixture was stirred for 17 hours at which timeit was carefully quenched with NH₄Cl (sat., 30 ml). The layers wereseparated and the aqueous phase was extracted with EtOAc (2×). Thecombined organics were washed with brine and dried (Na₂SO₄). Filtrationand concentration gave the crude product which was purified via flashcolumn chromatography (silica gel, 2% Et₃N/ether). After flushing theproduct through alumina with ether, the hydrochloride salt was preparedin ether/EtOAc (1:1, 40 ml, 1 drop IPA) with ethereal HCl to give 2.5 g(45%) of the desired product as a white solid, m.p.=163°-164° C.

ANALYSIS: Calculated for C₂₁H₃₁FN₂O₂.HCl: 63.22% C; 8.08% H; 7.02% N;Found: 62.97% C; 7.95% H; 7.01% N

EXAMPLE 187N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-nitrophthalimidefumarate

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.09g, 7.9 mmol) and 3-nitrophthalic anhydride (1.6 g, 8.3 mmol, 1.05 eq) indimethylformamide (DMF, 20 ml) was heated at 135° C. for 3 hours. Thesolvent was removed on a rotary evaporator under vacuum and furtherdried on a vacuum pump. The residue was purified by flash chromatographyover a silica gel column (SiO₂, 35 g; eluted with dichloromethane, 300ml, and 3% C;H₃OH in DCM, 300 ml). The product thus obtained, 2.01 g,was dissolved into DCM (15 ml) and ethanol (5 ml) and was treated with asolution of fumaric acid (530 mg, 1.0 eq) in ethanol (15 ml). Thecrystals were collected and weighed: 2.03 g, m.p.=237°-239° C.

ANALYSIS: Calculated for C₂₂H₁₉FN₄O₅.C₄H₄O₄: 56.32% C; 4.18% H; 10.10%N; Found: 55.94% C; 4.23% H; 9.87% N

EXAMPLE 188N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-hydroxyphthalimidehydrochloride

A mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (5 g,18.9 mmol), 4-hydroxyphthalic acid (4.14 g, 1.2 eq), anddicyclohexylcarbodiimide (DCC, 8.61 g, 4.18 mmol) in dimethylformamide(50 ml, DMF) was stirred and heated at 75° C. for 18 hours. The mixturewas cooled, and the solids (DCU) were filtered and rinsed withdichloromethane (DCM). The solution was concentrated down to dryness.The residue was dissolved into dichloromethane (100 ml) and theinsolubles, which contained the product also, were filtered andcollected. The solution was concentrated down to 50 ml and loaded onto aflash chromatography column (SiO₂, 50 g; eluted with DCM, andmethanol:DCM mixture). The desired product was collected as a pinkishsolid, 1.71 g. This solid was converted to the hydrochloride salt inethanol with an HCl in ether solution (1M, 5 ml). The crystals werecollected and dried; weight: 1.2 g; m.p.=272°-275° C. dec.

ANALYSIS: Calculated for C₂₂H₂₀FN₃O₄.HCl: 59.26% C; 4.75% H; 9.42% N;Found: 59.08% C; 4.60% H; 9.34% N

EXAMPLE 189(±)-6-Fluoro-3-[1-(3-hydroxybutyl)-4-piperidinyl]-1,2-benzisothiazolehydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (3.9 g, 17mmol), K₂CO₃ (2.3 g, 17 mmol, (+)-3-hydroxybutyl tosylate (4.0 g, 16mmol) and CH₃CN (100 ml) was stirred at reflux under N₂ for 5 hours. Thecooled reaction was filtered through Celite and the cake was rinsed withEtOAc. The filtrate was concentrated to afford 6.7 g of a red oil.Purification via preparative HPLC (Water's Associates Prep LC/System500, using 2 silica gel columns and 10% MeOH—CH₂Cl₂) provided 2.5 g of abeige solid. The product was dissolved in anhydrous Et₂O and a minimalamount of MeOH and the solution was acidified with ethereal HCl.Additional Et₂O was added to precipitate 1.9 g of the HCl salt.Recrystallization from MeOH-Et₂O gave 1.7 g and a secondrecrystallization from CH₂CN yielded 1.0 g (18%) of a light beigepowder, m.p.=182°-184° C.

ANALYSIS: Calculated for C₁₆H₂₁FN₂OS.HCl: 55.72% C; 6.43% H; 8.12% N;Found: 55.83% C; 6.54% H; 8.19% N

EXAMPLE 190 Decanoic acid1,1-diethyl-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylester hydrochloride

To a solution of6-fluoro-3-[1-(3-hydroxy-3-ethylpentyl)-4-piperidinyl]-1,2-benzisoxazole(2.5 g, 7.48 mmol) in DCM (100 ml) was added decanoyl chloride (1.5 ml,7.48 mmol) at 0 C, under nitrogen. The reaction mixture was stirred for4 days at which time it was poured into NaHCO₃ (sat., 50 ml). The layerswere separated and the aqueous phase was extracted with DCM (2×). Thecombined organics were dried, filtered and concentrated to give thecrude product which was purified via flash column chromatography (silicagel, 20-40% EtOAc/DCM). The product containing fractions wereconcentrated to give 3.0 g (81%) of the desired product as a yellow oil.The hydrochloride salt was prepared in anhydrous ether (60 ml) andisopropanol (1 ml) with ethereal HCl. The white salt was filtered andwashed with anhydrous ether, m.p.=159°-161° C.

ANALYSIS: Calculated for C₂₉H₄₅FN₂O₃.HCl: 66.33% C; 8.83% H; 5.33% N;Found: 66.45% C; 9.01% H; 5.31% N

EXAMPLE 191N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-naphthalimide

A mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.0 g,7.58 mmol), and 2,3-naphthalenedicarboxylic anhydride (1.58 g, 7.95mmol) in dimethylformamide (20 ml, DMF) was heated at 150° C. for 2hours. At the end, the mixture was cooled and the solvent was removed todryness. The residue was purified by flash chromatography over silicagel column (60 g of SiO₂, eluted with dichloromethane (DCM), and 1.5%C;H₃OH in DCM). The product crystallized out on concentration; weight:1.6 g (47%). Recrystallization from chloroform:ethanol gave 1.38 g ofoff-white crystals, m.p.=192°-193° C.

ANALYSIS: Calculated for C₂₆H₂₂FN₃O₃: 70.42% C; 5.00% H; 9.48% N; Found:69.85% C; 4.59% H; 9.27% N

EXAMPLE 1922,3-Dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-hydroxy-3-methyl-1H-isoindol-1-onefumarate

To the solution ofN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide(6.2 g, 15.87 mmol) in tetrahydrofuran (THF, 80 ml) was added dropwise asolution of methylmagnesium bromide (3M, 6.5 ml, 1.2 eq) in ether atroom temperature under N₂. The mixture was stirred at 55° C. for 16hours. The reaction mixture was treated with NH₄Cl solution (10 ml) andpartitioned between brine and ethyl acetate. The EtOAc solution waswashed with brine and dried. Filtration and concentration gave a crudeproduct (3.9 g). This crude product was purified on a flashchromatography column (40 g, SiO₂; eluted with 0.5% C;H₃OH in DCM). Thepure product (1.75 g, 27%) thus obtained was treated with fumaric acid(500 m, 1.0 eq) in ethanol to yield 1.8 g, m.p.=167°-168° C.

ANALYSIS: Calculated for C₂₃H₂₄FN₃O₃.C₄H₄O₄: 61.71% C; 5.37% H; 8.00% N;Found: 61.47% C; 5.67% H; 7.82% N

EXAMPLE 1932,3-Dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-methylene-1H-isoindol-1-onehydrochloride

To the solution of2,3-dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-hydroxy-3-methyl-1H-isoindol-1-one(4.88 g, 11.9 mmol) in chloroform (50 ml) was added HCl.ether (1M, 20ml) solution. A precipitate formed. This mixture was stirred for 18hours at room temperature. The mixture was basified with triethylamineand washed with brine. The organic solution was dried and concentratedto a crude material. The purification was done by flash chromatographyover silica gel column (SiO₂, 60 g; eluted with DCM). The pure productthus obtained weighed 3.28 g (70%). Treatment with HCl.ether solution inethanol gave 1.52 g of white crystals, m.p.=261°-263° C.

ANALYSIS: Calculated for C₂₃H₂₀FN₃O.HCl: 64.56% C; 5.42% H; 9.82% N;Found: 64.47% C; 5.51% H; 9.27% N

EXAMPLE 1941-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]cyclohexanolhydrochloride

To pentamethylene bis(magnesium bromide) (35.0 ml, 17.5 mmol, 0.5M inTHF) was added a solution of ethyl3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (5.6 g,17.5 mmol) in THF (100 ml) at 0 C., under nitrogen-mild exotherm. Thereaction mixture was warmed to room temperature and stirred for 17 hoursat which time it was carefully quenched with NH₄Cl (sat., 50 ml). Theprecipitated salts were dissolved into water (25 ml) and the layers wereseparated. The aqueous phase was extracted with EtOAc (2×) and thecombined organics were then dried (Na₂SO₄). Filtration and concentrationgave the crude product which was purified via flash columnchromatography (silica gel, 50% EtOAc/DCM then 100% EtOAc) to give 2.8 g(46%) of the desired product as a white solid. The hydrochloride saltwas prepared in anhydrous ether (125 ml) and methanol (15 ml) withethereal HCl, m.p.=210° C. (dec.).

ANALYSIS: Calculated for C₂₀H₂₇FN₂O₂.HCl: 62.74% C; 7.37% H; 7.32% N;Found: 62.85% C; 7.53% H; 7.14% N

EXAMPLE 1955-[4-(6Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]-3-ethyl-3-hydroxypentanehydrochloride

To a stirred solution, under N₂, of ethyl3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propionate (5.3 g,16 mmol) in THF (200 ml), was added dropwise, ethyl magnesium bromide(15.7 ml of a 3.0M solution in Et₂O). The reaction was stirred atambient temperature for 16 hours and then following cooling in an icebath, a saturated solution of NH₄Cl was added dropwise. The aqueousmixture was extracted with EtOAc, and the extract was washed (H₂O),dried (MgSO₄) and the solvent was concentrated to afford 5.8 g of ayellow oil. The oil was chromatographed on a preparative HPLC, upon asilica gel column, eluting with 6% MeOH/CH₂Cl₂. Concentration of theappropriate fractions yielded 3.7 g of a yellow oil. The oil wasdissolved in Et₂O and ethereal HCl was added to precipitate 4.0 g of awhite salt. The salt was recrystallized twice from EtOH-Et₂O to afford1.4 g (22%) of the alcohol as a white solid, m.p.=207°-209° C.

ANALYSIS: Calculated for C₁₉H₂₇FN₂OS.HCl: 58.98% C; 7.29% H; 7.24% N;Found: 58.95% C; 7.63% H; 7.11% N

EXAMPLE 196 Ethyl3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propionate hydrochloride

To a stirred suspension of 6-fluoro-3-(4-piperazinyl)-1H-indazole (9.9g, 45 mmol), K₂CO₃ (6.8 g, 49 mmol) and CH₃CN (210 ml) under N₂ wasadded, dropwise, ethyl 3-bromopropionate (8.1 g, 45 mmol) in CH₃CN (20ml). After complete addition, the reaction was stirred at reflux for16.5 hours. A TLC revealed remaining starting indazole; therefore,triethylamine (1.5 g, 14 mmol) was added dropwise to the cool reactionmixture. The reaction was stirred at reflux for 1 hour longer with noadditional change by TLC. The reaction was cooled, filtered, and thefiltrate concentrated to yield 14.6 g of an off-white solid. Thematerial was purified by preparative HPLC (Water's Associates PrepLC/System 500 A using 2 silica gel columns and 6.5% MeOH—CH₂Cl₂ aseluent). Concentration of appropriate fractions gave 8.1 g (51%) of agrey-white solid. A 1.5 g sample was dissolved in MeOH (45 ml) and wasacidified with ethereal HCl. The solution was stirred for 5 minutes andanhydrous ether (50 ml) was added. Within one minute the HCl saltprecipitated. More anhydrous ether (100 ml) was added and the salt wascollected and dried to yield 1.5 g of a white solid. Recrystallizationfrom ethanol provided 1.2 g (37%) of fluffy white crystals,m.p.=224°-226° C.

ANALYSIS: Calculated for C₁₆H₂₁FN₄O₂.HCl: 53.86% C; 6.21% H; 15.70% N;Found: 53.81% C; 5.88% H; 15.37% N

EXAMPLE 1974-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylbutyldecanoate fumarate

To a mixture of4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-2-butanol(4.68 g, 15.3 mmol) and triethylamine (2.23 g, 22.3 mmol) in chloroform(20 ml) was added decanoyl chloride (3.5 g, 18.4 mmol, 1.2 eq) dropwiseat 0° C. The reaction was stirred at ambient temperature for 4 hours.The solvent was removed. The residue was purified by flashchromatography over a silica gel column (SiO₂, 65 g, eluted with DCM, 1l, 1% C;H₃OH in DCM, 1 l). The product thus purified weighed 5.7 g (80%)as an oil. This oily product was converted to the fumarate salt inethanol with fumaric acid (1.51 g, 1.0 eq) to yield 3.34 g,m.p.=133°-134° C.

ANALYSIS: Calculated for C₂₇H₄₁FN₂O₃.C₄H₄O₄: 64.56% C; 7.87% H; 4.86% N;Found: 64.24% C; 7.74% H; 4.78% N

EXAMPLE 1982-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-methyl-1H-isoindol-1-onehydrochloride

A mixture of2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-3-methyl-1H-isoindol-1-one(3.96 g, 9.7 mmol) and lithium aluminum hydride (1.1 g, 50% in oil, 1.5eq) in tetrahydrofuran (50 ml) was stirred at room temperature for 16hours. The mixture was quenched carefully with a small amount of ice,then was diluted with ethyl acetate (200 ml). The mixture was stirredfor 20 minutes. The insolubles were filtered. The organic solution wasdried over MgSO₄ and concentrated down to a yellow oil (4.5 g). This oilwas purified by flash chromatography over silica gel column (SiO₂, 58 g;eluted with DCM, 1 l, and 1% CH₃OH in DCM). Only 1.91 g of desiredproduct was obtained. This material was treated with HCl (1M HCl inether, 6 ml) in ethanol followed by isopropyl ether to yield 1.48 g(36%), m.p.=213°-215° C.

ANALYSIS: Calculated for C₂₃H₂₄FN₃O₂.HCl: 64.25% C; 5.86% H; 9.77% N;Found: 63.88% C; 5.74% H; 9.44% N

EXAMPLE 1991-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]cyclopentanolhydrochloride

In a flame-dried 500 ml round-bottom flask, equipped with additionfunnel and condenser, was placed magnesium metal (3.4 g, 140 mmol) andanhydrous ether (20 ml). A solution of 1,4-dibromobutane (4.4 ml, 36.5mmol) in anhydrous ether (10 ml) was then syringed into the additionfunnel and added dropwise to the magnesium metal. Initially no reactiontook place, but with the addition of a few crystals of iodine and gentleheating the Grignard reagent began to form. The rate of addition wassuch that a gentle reflux was maintained. Upon complete addition, theGrignard was stirred for 0.5 hours. A solution of3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (9.0 g,28.1 mmol) in THF (75 ml) was then added (dropwise, exothermic) at roomtemperature and stirred for 21.5 hours. The reaction mixture wascarefully quenched with NH₄Cl (sat., 100 ml) and the precipitatedmagnesium salts were dissolved into water (50 ml). The layers wereseparated and the aqueous phase was extracted with EtOAc (2×). Thecombined organics were dried (Na₂SO₄), filtered and concentrated to givethe crude product. Purification via flash column chromatography (silicagel, 50% EtOAc/DCM) gave 6.2 g (67%) of the desired product as a whitesolid. The hydrochloride salt was prepared in EtOAc (50 ml), ether (40ml), and methanol (5 ml) with ethereal HCl, m.p.=185°-188° C.

ANALYSIS: Calculated for C₁₉H₂₅FN₂O₂.HCl: 61.87% C; 7.10% H; 7.59% N;Found: 61.79% C; 7.09% H; 7.53% N

EXAMPLE 2004-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]-2-hydroxy-2-methylbutanehydrochloride

To a stirred solution of ethyl3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propionate (5.0 g, 16mmol), in THF (120 ml) under N₂ was added, dropwise, methylmagnesiumbromide (15.6 ml of a 3.0M solution in Et₂O; 0.047 mol). The temperaturewas maintained below 30° C. during the addition by using a water bath.After complete addition, the reaction was stirred at ambient temperaturefor 5 hours. The reaction was cooled in an ice bath and saturated NH₄Cl(25 ml) was added. The mixture was extracted with EtOAc, and the EtOAcextract was washed with H₂O, dried with Na₂SO₄ and concentrated to yield5.0 g of a white solid. The product was recrystallized from EtOAc toyield 3.8 g of white crystalline flakes. The compound was dissolved inanhydrous Et₂O (200 ml) and MeOH (20 ml) and the insolubles werefiltered away. The filtrate was acidified with ethereal HCl toprecipitate the salt. Additional anhydrous Et₂O (200 ml) was added andthe suspension was stirred 15 minutes. The solid was collected to yield4.5 g of a white powder. Two recrystallizations from MeOH gave 2.2 g.The concentrated mother liquid from the MeOH recrystallizations (2.0 g)was recrystallized from DMF to afford 1.2 g. The two samples werecombined and a final recrystallization from MeOH provided 3.0 g (57%) ofa white powder m.p.=254°-256° C.

ANALYSIS: Calculated for C₁₆H₂₃FN₄O.HCl: 56.06% C; 7.06% H; 16.34% N;Found: 55.99% C; 6.99% H; 16.27% N

EXAMPLE 201N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-aminophthalimidefumarate

A solution containing2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (6.8 g,25.7 mmol), dicyclohexyl carbodiimide (DCC, 8.2 g, 39 mmol) and4-aminophthalic acid (4.57 g, 25.2 mmol) in dimethylformamide (DMF, 100ml) was heated at 110° C. for 5 hours and kept at 65° C. for 18 hours.At the end of the reaction, the solids (DCU) were filtered and thesolvent was removed on a rotary evaporator using a vacuum pump. Theresulting crude product was purified by flash chromatography (SiO₂, 130g) and provided 7.5 g (83%) of the desired product. It was converted tothe fumarate salt which was recrystallized from ethanol and isopropylether: 7.1 g, m.p.=229°-230° C.

ANALYSIS: Calculated for C₂₂H₂₁FN₄O₃.C₄H₄O₄: 59.54% C; 4.80% H; 10.68%N; Found: 58.99% C; 4.79% H; 10.37% N

EXAMPLE 202N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6-pyrrolo-3,4-6]pyridine-5,7-dionefumarate

A solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (4.14 g,15.7 mmole) and 3,4-pyridinedicarboxylic anhydride (2.64 g, 17.7 mmol)in dimethylformamide (DMF, 100 ml) was heated at 130° C. for 18 hours.The solvent was removed on the rotary evaporator with a vacuum pump. Theresidue was dissolved into ethanol (250 ml) and the insolubles werefiltered. To the ethanol solution was added fumaric acid (1.82 g, 1.0eq), then the solution was concentrated to 120 ml. Isopropyl ether (120ml) was added and the mixture was stirred overnight. The white crystals(3.1 g, 48%), m.p.=203°-206° C., were collected and recrystallized againfrom ethanol to give 2.34 g of pure product, m.p.=208°-209° C.

ANALYSIS: Calculated for C₂₁H₁₉N₄O₃.C₄H₄O₄: 58.82% C; 4.54% H; 10.98% N;Found: 58.59% C; 4.67% H; 10.71% N

EXAMPLE 203N-[2,3-Epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinefumarate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50mmol), K₂CO₃ (7.5 g, 54 mmol) and epibromohydrin (9 g, 54 mmol) inacetonitrile (150 ml) was heated at reflux for 16 hours. The mixture wasfiltered and concentrated to dryness. The crude product was purified byflash chromatography (SiO₂, 180 g, eluted with methylene chloride (DCM),and 1-2% C;H₃OH in DCM). The material thus purified as off-white solidsweighed 8.7 g (63%). This material (3 g) was converted to fumarate saltin ethanol and isopropyl ether to give 3.27 g of white crystals,m.p.=145°-147° C.

ANALYSIS: Calculated for C₁₅H₁₇FN₂O₂.C₄H₄O₄: 58.16% C; 5.39% H; 7.14% N;Found: 57.93% C; 5.35% H; 7.02% N

EXAMPLE 2044-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propoxy]phenylmethyl ether

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.4 g, 20mmol) and 2,3-epoxypropyl-4-methoxyphenyl ether (3.7 g, 20.5 mmol) inisopropyl alcohol (80 ml) was heated to reflux for 2 hours. The mixturewas cooled and the crystals were collected to yield 6.81 g (85%),m.p.=134°-135° C.

ANALYSIS: Calculated for C₂₂H₂₅FN₂O₄: 65.99% C; 6.29% H; 7.00% N; Found:66.11% C; 6.31% H; 6.84% N

EXAMPLE 2053-[4-(6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]-2-hydroxy-1-propylphthalimide

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.5 g, 25mmol) and N-(2,3-epoxypropyl)phthalimide (5.1 g, 25.5 mmol) inisopropanol (100 ml) was heated at reflux for 4 hours and stirred at 65°C. for 18 hours. The reaction was cooled and the solvent was removed ona rotary evaporator. The white solids were dissolved in methylenechloride and purified on a silica gel column (110 g, eluted with 1%C;H₃OH in DCM, 1.5 l). The pure product thus obtained weighed 7.91 g,75%. Recrystallization from DCM and isopropyl ether yielded 4.0 g,m.p.=162°-163° C.

ANALYSIS: Calculated for C₂₃H₂₂FN₃O₄: 65.24% C; 5.24% H; 9.92% N; Found:65.00% C; 5.05% H; 9.77% N

EXAMPLE 2061-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-phthalimido-2-propyldeanoate fumarate

To a solution of3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propylphthalimide(6.26 g, 14.5 mmol), triethylamine (2.0 g, 20 mmol) in chloroform (200ml) was charged with decanoyl chloride (3.6 g, 18.9 mmol, 1.26equivalent) dropwise at room temperature. The mixture was stirredovernight. The mixture was concentrated and the crude product waspurified on a flash chromatography column. The product thus obtained asan oil (4.96 g, 59%). This oil was converted to fumarate salt in adilute ethanol solution to yield 2.0 g, m.p.=138°-140° C.

ANALYSIS: Calculated for C₃₃H₄₀FN₃O₅.C₄H₄O₄: 64.06% C; 6.39% H; 6.06% N;Found: 63.90% C; 6.39% H; 5.88% N

EXAMPLE 207N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-4methylphthalimidedihydrochloride

A solution of 2-[4-[(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]amine(1.9 g, 7.2 mmol), 4-methylphthalic anhydride (1.2 g, 7.4 mmol) and DMF(50 ml) was stirred at 75° C. for 5 hours. Most of the DMF was removedin vacuo and the resultant red oil was triturated with H₂O to produce abrown solid. The product was dissolved in CH₂Cl₂ and the organic extractwas washed with H₂O, dried with MgSO₄ and concentrated to afford 2.8 gof a foam. The compound was suspended in MeOH (50 ml) and made acidicwith ethereal HCl and the resultant solution was stirred for hour.Anhydrous Et₂O was added to precipitate 2.5 g of an off-white powder.This was combined with an additional sample (4.3 g total), and tworecrystallizations from MeOH-Et₂O provided 3.0 g (56%) of an off-whitepowder, m.p.=238°-241° C.

ANALYSIS: Calculated for C₂₂H₂₂Cl₂FN₅O₂.2HCl: 55.01% C; 5.04% H; 14.58%N; Found: 55.35% C; 5.09% H; 14.56% N

EXAMPLE 208N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-4-fluorophthalimidehydrochloride

A solution of 2-[4-[(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]amine(4.0 g, 15 mmol), 4-fluorophthalic anhydride (2.5 g, 15 mmol) and DMF(75 ml) was stirred at 75° C. under N₂ for 4 hours. The reaction wasconcentrated to yield 6.7 g of a brown solid. The product was suspendedin MeOH (150 ml) and was acidified with ethereal HCl. After stirring for30 minutes, anhydrous Et₂O was added and the resultant beige solid wascollected to yield 5.1 g. The compound was recrystallized fromMeOH-ether to give 3.8 g (56%) of an off-white powder, m.p.=282°-285° C.

ANALYSIS: Calculated for C₂₁H₁₉F₂N₅O₂.HCl: 56.32% C; 4.50% H; 15.64% N;Found: 56.07% C; 4.35% H; 15.63% N

EXAMPLE 209N-2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-(1-decanoyl)aminophthalimide

To a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-aminophthalimide(1.5 g, 3.67 mmol), triethylamine (0.46 mg, 4.6 mmol) in chloroform (30ml) was charged with decanoyl chloride (0.8 mg, 4.2 mmol) dropwise atroom temperature. The mixture was stirred for 1 hour. An additionalportion of decanoyl chloride (0.1 mg, 0.52 mmol) was added to completethe reaction. The mixture was concentrated down, and the crude productwas purified on a flash chromatography column (30 g of silica gel;eluted with dichloromethane (DCM) and 1% C;H₃OH in DCM). The oilyproduct was dissolved in ethanol and treated with ether to yield whitecrystals 1.04 g (47.5%), m.p.=159°-160° C.

ANALYSIS: Calculated for C₃₂H₃₉N₄₀O₄: 68.31% C; 6.99% H; 9.96% N; Found:68.47% C; 7.27% H; 9.95% N

EXAMPLE 210N-2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-(1-decanoyl)oxyphthalimidefumarate

To a mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-hydroxyphthalimide(5.1 g, 12.5 mmol), triethylamine (2.09 g, 1.67 equiv) in chloroform(150 ml) was charged decanoyl chloride (3.8 g, 20 mmol) dropwise at roomtemperature. The mixture was stirred at room temperature overnight (16hours). The solution was diluted with methylene chloride (DCM, 150 ml)and washed with brine. The organic solution was dried and concentratedto a crude mixture. Purification on a flash chromatography column (SiO₂,100 g, eluted with DCM and 1% C;H₃OH in DCM) yielded a colorless oil(5.0 g, 71%). This product was treated with fumaric acid (1.0 g) inethanol (30 ml) and isopropyl ether (15 ml) to give 3.1 g of whitecrystals, m.p.=108°-110° C.

ANALYSIS: Calculated for C₃₂H₃₈FN₃O₅.C₄H₄O₄: 63.61% C; 6.23% H; 6.18% N;Found: 63.71% C; 6.30% H; 6.25% N

EXAMPLE 2112-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl-2,3-dihydro-3-hydroxy-1H-isoindol-1-onehemifumarate

To a stirred suspension ofN2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (4.0g, 10 mmol) in MeOH (125 ml) and CH₂Cl₂ (15 ml) under N₂, was addedNaBH₄ (0.89 g, 23 mmol) in one portion. The reaction was stirred atambient temperature for 45 minutes and was concentrated to yield a dampwhite solid. Flash chromatography using silica gel and 5% MeOH—CH₂Cl₂increasing to 10% MeOH—CH₂Cl₂ as eluent, provided 4.5 g of a beigeliquid. The liquid was dissolved in MeOH (50 ml), and the solution wasacidified with ethereal HCl. Anhydrous Et₂O was added to precipitate 2.9g of a white solid. This was combined with an additional sample (4.6 gtotal) and was suspended in H₂O (100 ml). NaHCO₃ was added to attainpH˜7 and the gummy mixture was extracted with CH₂Cl₂. The CH₂Cl₂ extractwas dried with MgSO₄ and concentrated to yield 4.1 g of a white foam.The compound was purified by preparative HPLC (Water's Associates PrepLC/System 500, using 2 silica gel columns and 5% Et₂NH-EtOAc as eluent).Concentration of appropriate fractions gave 2.1 g (5.3 mmol) of a beigefoam. The compound was dissolved in EtOAc (50 ml) and the insolubleswere filtered away. The filtrate was gently warmed and the fumaric acid(0.70 g, 6.0 mmol) was added. After stirring at mild reflux for 30minutes and at ambient temperature for 1 hour, the mixture was dilutedwith anhydrous Et₂O (50 ml).

The resultant solid was collected and dried to yield 2.2 g.Recrystallization from ethanol-ether provided 1.1 g (16%) of thehemi-fumarate salt as a slightly off-white solid m.p.=165°-168° C.

ANALYSIS: Calculated for C₂₁H₂₂FN₅O₂.0.5C₄H₄O₄: 60.91% C; 5.35% H;15.45% N; Found: 60.41% C; 5.35% H; 15.22% N

EXAMPLE 2124-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl-2-hydroxy-1-propoxy]-3-methoxyphenylmethanone

A stirred mixture of 4-(2,3-epoxypropoxy)-3-methoxyphenyl methanone (4.5g, 22.5 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.36 g,24.3 mmol) in isopropyl alcohol (150 ml) was heated at 55° C. for 16hours. The mixture was cooled and the solvent was removed on a rotaryevaporator. The residue was purified by flash chromatography over asilica gel column (SiO₂, 80 g; eluted with dichloromethane, DCM, and 1%C;H₃OH in DCM). The oil thus obtained solidified quickly, weight: 9.47g. Recrystallization from ethanol and isopropyl ether, then tolueneprovided 8.6 g (86%) of white crystals, m.p.=107°-108° C.

ANALYSIS: Calculated for C₂₄H₂₇FN₂O₅: 65.15% C; 6.15% H; 6.33% N; Found:65.35% C; 6.04% H; 6.05% N

EXAMPLE 2131-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-propanonehydrochloride

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (7.45 g, 33.4mmol), K₂CO₃ (5.5 g) and bromo-2,2-dimethoxypropane (6.84 g, 37.6 mmol)in acetonitrile (200 ml) was heated and stirred at reflux for 4 hours.An additional charge of bromo-2,2-dimethoxypropane (5.1 g, 28 mmol) wasadded and the mixture was refluxed overnight. After being cooled to roomtemperature, the mixture was filtered, and the solvent was removed on arotary evaporator. The residue was purified by flash chromatography overa silica gel column (SiO₂, 100 g; eluted with dichloromethane, DCM, and1% C;H₃OH in DCM). The oil product thus obtained weighed 2.2 g (24%).The oil product was dissolved into ethanol (10 ml) then was treated withHCl in ether solution (1M, 9 ml) at room temperature. The crystals werecollected, 2.08 g, m.p.=220°-223° C. dec.

ANALYSIS: Calculated for C₁₅H₁₇FN₂O₂•HCl: 57.60% C; 5.80% H; 8.96% N;Found: 57.49% C; 5.97% H; 8.67% N

EXAMPLE 2141-[(4-Aceto-2-methoxy)phenoxyl-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-propyldecanoate fumarate

To a stirred mixture of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propoxy]-3-methoxyphenylmethanone (3.64 g, 8.23 mmol, triethylamine (1.6 g, 16 mmol) inchloroform (150 ml) was added decanoyl chloride (2.35 g, 12.4 mmole, 1.5eq) dropwise at room temperature. The mixture was then heated at refluxfor 1 hour The mixture was cooled and diluted with methylene chloride(DCM) and washed with water and brine. The organic solution was driedand concentrated to a crude mixture. Purification on a flashchromatography column (SiO₂, 65 g; eluted with DCM, 0.4 l and 1% C;H₃OHin DCM, 0.6 l) yielded a colorless oil: 3.29 g (67%). This product wastreated with fumaric acid (623 mg) in ethanol (10 ml) and isopropylether (50 ml) to give 2.64 g of a white solid, m.p.=109°-110° C.

ANALYSIS: Calculated for C₃₄H₄₅FN₂O₆•C₄H₄O₄: 64.03% C; 6.93% H; 3.93% N;Found: 63.86% C; 6.88% H; 3.74% N

EXAMPLE 215N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]thiaphthalimide

A mixture ofN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide(3.93 g, 10 mmol) and2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadephosphetane-2,4-disulfide (2.02g, 5 mmol, 1 equiv. Lawesson's Reagent) is stirred and heated inanhydrous tetrahydrofuran for 3 hours at 60° C. The reaction mixture isevaporated on silica gel and purified by chromatography on a silica gelcolumn. The product is further purified by recrystallization to affordN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]thiaphthalimide.

EXAMPLE 216

By using substantially the same procedure as described in Example 215except that 10 mmol (2 equiv.) of Lawesson's Reagent is used and thereaction time at 60° C. is extended to 5 hours there is obtainedN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-1,3-bis-thiaphthalimide.

EXAMPLE 217N-[2-[4-(6-Fluoro-1-decanoyl-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimidemaleate

To a stirred suspension of NaH (0.50 g of a 50% oil dispersion, 12.5mmol) in DMF (10 ml) under N₂ and cooled to −15° C., was added dropwise,N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (4.0g, 10.2 mmol) dissolved in DMF (45 ml) over 45 minutes so that thetemperature did not exceed −8° C. The reaction was stirred for 1 hourallowing the temperature to warm to 0° C. The reaction was cooled to−12° C. and a solution of decanoyl chloride (2.9 g, 15.3 mmol) in DMF(13 ml) was added dropwise so that the temperature remained below −5° C.After complete addition, the reaction was stirred at ambient temperaturefor 18 hours. The reaction was poured into ice-cold H₂O (125 ml) and theaqueous mixture was extracted with EtOAc. The EtOAc extract was washedwith H₂O/Brine (3×), dried with MgSO₄ and concentrated to yield 5.7 g ofa beige oil that readily crystallized. This was combined with anothersample (6.4 g total) and purification via flash chromatography, oversilica gel using 3% MeOH/CH₂Cl₂ as eluent, afforded 4.9 g (78%) of awhite solid. Another previously purified sample was combined with this(6.3 g, 11.5 mmol total) and the product was dissolved in hot absoluteethanol (100 ml). Maleic acid (1.4 g, 12.1 mmole) was added and thesolution was stirred at a mild reflux for 30 minutes. The reaction wasconcentrated to a white slush that was diluted with petroleum ether (100ml) and stirred for ca 2 hours. The resultant solid was collected toyield 5.5 g of shiny white crystals. The salt was recrystallized twicefrom absolute ethanol to afford 4.3 g and a third recrystallization fromCH₃CN gave 3.8 g (39%) of the analytically pure maleate salt as a whitesolid, m.p.=154°-156° C.

ANALYSIS: Calculated for C₃₁H₃₈FN₅O₃•C₄H₄O₄: 63.34% C; 6.38% H; 10.55%N; Found: 63.46% C; 6.33% H; 10.60% N

EXAMPLE 2182-[4-[6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propyl]aminedihydrochloride hemihydrate (A)2-[4-[6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propionitrile

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidine (10 g, 45.4mmol); 2-chloropropionyl (10 g, 112 mmol), K₂CO₃ (9.4 g, 1.5 eq) inacetronitrile (100 ml) was stirred and heated at 80° C. for 16 hours.The mixture was filtered and concentrated to dryness. The crude solidswere purified by flash chromatography (SiO₂, 160 g; eluted withmethylene chloride, (DCM) 1.5 l; and 1% C;H₃OH in DCM, 1 l). The whitesolid material thus obtained weighed 10.1 g and was recrystallized fromethanol and isopropyl ether to yield 5.1 g, m.p.-133°-134° C.

ANALYSIS: Calculated for C₁₅H₁₆FN₃O: 65.92% C; 5.90% H; 15.37% N; Found:65.92% C; 5.85% H; 15.52% N

(B) 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]aminedihydrochloride hemihydrate

To a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionitrile (6.7g, 24.5 mmol) in THF (200 ml) was added lithium aluminum hydride (3.6 g,50% in oil, 2 eq) in portions under N₂ at room temperature for 3.5hours. At the end of the reaction, the excess of LAH was carefullyhydrolyzed with ice-chips (7 ml) under N₂. A solution of 15% N;aOH (2ml) was added, then the mixture was stirred for 30 minutes. Theinsolubles were filtered and the organic solution was concentrated downto a pale oil (7.6 g) which partially solidified. A sample (1.5 g) ofthis mixture was dissolved into ethanol and was treated with HCl (6 ml,1M in ether). The white solid which precipitated was collected andrecrystallized from ethanol to give 708 mg, m.p. 215°-217° C. of thedihydrochloride hemihydrate. Calculated for C₁₅H₂₀FN₃O.2HCl.0.5H₂O:50.14% C; 6.45% H; 11.69% N; 2.50% H₂O Found: 49.94% c 6.17% H; 11.11%N; 2.12% H₂O

EXAMPLE 219N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimidehydrochloride

To a stirred mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]amine 2.56g, 9.52 mmol) and triethylamine (1.35 g, 13.5 mmol) in chloroform (150ml) was added phthalic anhydride (1.61 g, 10.9 mmol). The mixture wasstirred at room temperature for 4 hours. At the end of the reaction thesolvent was evaporated on a rotary evaporator and the crude residue wasdried in vacuo. The purification was done by flash chromatography over asilica gel column (40 g, SiO₂, eluted with methylene chloride, thenincrease the MeOH concentration to 2%). The pure product thus obtained(2.18 g) was combined with another batch of same quality material (1.53g) and then was converted to the hydrochloride salt with HCl in ethersolution. The white solid was recrystallized from methanol to give 3.12g, m.p.=275°-277° C.

ANALYSIS: Calculated for C₂₃H₂₂FN₃O₃•HCl: 62.23% C; 5.22% H; 9.47% N;Found: 61.93% C; 5.32% H; 9.46% N

EXAMPLE 220N-[2-[4-(1-Decanoxycarbonyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimidehydrochloride

A mixture of decanyl chloroformate (2.4 g, 11 mmol), andN-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (3.9g, 10 mmol) was warmed on the steam bath for 15 minutes. The reactionwas allowed to cool to ambient temperature, and then ether was added tothe residue. The resulting solid was filtered to afford N-[2-[4-(1-decanoxy-6-fluoro-1 H-indazol-3-yl )-1-piperazinyl]ethyl]phthalimidehydrochloride.

EXAMPLE 221N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]3-methoxyphthalimidehydrochloride

A mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-hydroxyphthalimidehydrochloride (4.36 g, 10.33 mmol) and K₂CO₃ (3.6 g, 26 mmol) inmethanol was stirred for 15 minutes. Then dimethylsulfate (4.0 g, 3.17mmol) was added, followed by potassium t-butoxide (1.1 g, 10 mmol) andthe mixture was stirred at room temperature for 4 hours. The reactionmixture was concentrated and the residue was extracted with DCM (400ml). The organic layer was filtered and concentrated and the resultingresidue was chromatographed on silica gel (47 g SiO₂), eluting with DCMand MeOH:DCM mixture. The resulting product (1.4 g) was converted to thehydrochloride salt in ethanol with 1N-HCl in ether. The resulting whitesolid was recrystallized from methanol to give 1.12 g, mp=247°-250° C.

ANALYSIS: Calculated for C₂₃H₂₂FN₃O₄•HCl: 60.07% C; 5.04% H; 9.14% N;Found: 59.79% C; 5.05% H; 8.98% N

EXAMPLE 2226-Fluoro-3-[1-[3-(2,5-dimethoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazolehydrochloried (A) 2-(3-Chloropropoxy)-1,4-dimethoxybenzene

A mixture of 2,5-dimethoxyphenol (29 g, 0.19 mol), K₂CO₃ (35 g),3-chlorobromopropane (38.5 g, 0.25 mol) and acetone (250 ml) was stirredand refluxed for 6 hours, and then stirred at ambient temperature for 16hours. The reaction as filtered, and the filtrate was concentrated to anorange liquid. The liquid was taken up into Et₂O, and the organic layerwashed with 1N NaOH, H₂O, dried (MgSO₄) and was concentrated to yield37.8 g of an orange solid. An 11.7 g sample of this solid was flashchromatographed on silica gel (180 g) with 5% EtOAc/CH₂Cl₂ as eluent.Concentration of similar fractions gave 7.2 g of white, waxy solid,which was recrystallized from petroleum ether to afford a white solid,m.p. 48°-50° C.

ANALYSIS: Calculated for C₁₁H₁₅ClO₃; 57.27% C; 6.55% H; Found: 57.19% C;6.52% H

(B)6-Fluoro-3-[1-[3-(2,5-dimethoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazoleHydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxzole (3.0 g, 14.0mmol), 2-(3-chloropropoxy)-1,4-dimethoxybenzene, K₂CO₃ (2.1 g) andacetronitrile (50 mL) was stirred and refluxed for 24 hours. Thereaction was filtered and the filtrate was concentrated to 5.0 g of anoil. The oil was chromatographed on a preparative HPLC on a silica gelcolumn with 5% MeOH—CH₂Cl₂ as eluent. Concentration of the appropriatefractions afforded 4.6 g of an oil, which, with ethereal HCl, wasconverted to 4.0 g of a white hydrochloride salt. The salt wasrecrystallized twice from EtOH to yield 2.9 g of product as a whitesolid, m.p. 186°-188° C.

ANALYSIS: Calculated for C₂₃H₂₇FN₂O₄•HCl: 61.26% C; 6.26% H; 6.21% N;Found: 61.14% C; 6.38% H; 6.15% N

EXAMPLE 2234-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2hydroxy-5-methoxy-alpha-methylbenzenemethanol(A). 1-[4-(3-Chloropropoxy)-2-hydroxy-5-methoxyphenyl]ethanone

A mixture of 2,4-dihydroxy-5-methoxyacetophenone (1.4 g, 7.7 mmol).K₂CO₃ (1.4 g, 10.0 mmol), 3-chlorobromopropane (1.6 g, 10.0 mmol) andacetone (25 mL) was stirred and refluxed under N₂ for 16 hours. Thereaction was poured into H₂O, and the aqueous suspension was extractedwith ethyl acetate. The extract was washed (H₂O, brine) dried (MgSO₄)and concentrated to yield 1.4 g of an off-white solid. Recrystallizationtwice from ethanol afforded 0.4 g of the alkylated phenol as a solid,m.p. 99°-101° C.

ANALYSIS: Calculated for C₁₂H₁₅ClO₄: 55.71% C; 5.84% H; Found: 55.61% C;5.92% H

(B)1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.2 g, 19mmol), 1-[4-(3-chloropropoxy)-2-hydroxy-5-methoxyphenyl]ethanone (5.0 g,19 mmol), NaHCO₃ (1.8 g, 20 mmol) and acetronitrile (120 mL) was stirredand refluxed for 16 hours. The reaction was filtered and the filtratewas concentrated to a dark oil. The oil was taken up in anhydrous etherand ethereal HCl was added to precipitate 8.7 g of an off-whitehydrochloride salt. A 2.0 g sample of the salt was converted to its freebase and chromatographed by preparative HPLC (silica gel with 5%MeOH/CH₂Cl₂ as eluent). Concentration of the desired fractions gave 1.1g of a white solid, which was recrystallized from EtOH to yield 0.85 gof the product, m.p. 122°-124° C.

ANALYSIS: Calculated for C₂₄H₂₇FN₂O₅: 65.15% C; 61.5% H; 6.33% N; Found64.93% C; 6.23% H; 6.20% N

(C)4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxy-alpha-methylbenzenemethanol

To a stirred solution of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-5-methoxyphenyl]ethanone(3.0 g, 6.8 mmol) in tetrahydrofuran/ethanol (70 ml, 4:3) was addedsodium borohydride (0.26 g, 6.8 mmol). The reaction was stirred atambient temperature for 0.75 hours, and then concentrated to afford athick oil. The oil was triturated with H₂O and the aqueous suspensionwas extracted with CH₂Cl₂. The extract was washed with H₂O, dried(MgSO₄) and concentrated to afford 3.4 g of a white solid. The solid wasrecrystallized from MeOH and then from EtOH to yield 0.80 g of solid,m.p. 156°-158° C.

ANALYSIS: Calculated for C₂₄H₂₉FN₂O₅: 64.85% C; 6.58% H; 6.30% N; Found:64.73% C; 6.58% H; 6.13% N

EXAMPLE 224N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimidefumarate

A solution of fumaric acid (448 mg, 3.86 mmol) in ethanol was added to ahot solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide(1.52 g, 3.86 mmol) in ethanol. The solution was cooled and the crystalswere collected to yield 1.9 g. Recrystallization once from ethanolyielded 1.15 g of the fumarate salt, m.p. 231°-232° C.

ANALYSIS: Calculated for C₂₂H₂₀FN₃O₃•C₄H₄O₄: 61.29% C; 4.75% H; 8.25% N;Found: 61.03% C; 4.68% H; 8.38% N

EXAMPLE 225N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide(A) 1-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxybutane

A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.5g, 25 mmol) and 1,2-expoxybutane (1.89 g, 26.3 mmol) in isopropylalcohol (100 ml) was heated at 65 C. for 2 days. This mixture was cooledand the solvent was removed to leave a brown oil which was purified byflash chromatography over a silica gel column (SiO₂, 70 g; eluted withDCM, 1 l and MeOH:DCM 2% : 98%) to give an off-white solid weighing 6.3g. Recrystallization from hot ethanol yielded 1.96 g of fine crystals,m.p. 87°-88° C.

ANALYSIS: Calculated for C₁₆H₂₁FN₂O₂: 65.73% C; 7.24% H; 9.58% N; Found:65.83% C; 7.12% H; 9.54% N

(B)N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide

A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF(50 ml) was added dropwise to a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (6.9 g, 23.6mmol), phthalimide (4.16 g, 1.2 eq), and triphenylphosphine (7.4 g, 28.3mmol) in THF (200 ml) at room temperature. The solution was stirred atroom temperature for 24 hours. After the reaction, the solvent wasstripped to dryness. The residue was stirred in ether (200 ml) and theinsolubles were removed by filtration. The oily residue fromconcentration of the ether solution was purified by two flashchromatography (SiO₂, 75 g, eluted with dichloromethane, DCM, and 1-2%C;H₃OH in DCM) and (100 g of SiO₂; eluted with DCM, 11, and 1% CH₃OH inDCM, 1.2 l). Two close compounds were separated and the top compound onTLC (1.6 g) was recrystallized from isopropyl ether to yield 0.76 g ofwhite crystals, m.p. 86°-88° C.

ANALYSIS: Calculated for C₂₄H₂₄FN₃O₃: 68.39% C; 5.74% H; 9.97% N; Found:68.47% C; 5.67% H; 9.97%; N

EXAMPLE 226N-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimidehydrochloride

A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF(50 ml) was added dropwise to a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butanol (6.9 g,23.6 mmol), phthalimide (4.16 gm, 1.2 eq), and triphenylphosphine (7.4g, 28.3 mmol) in THF (200 ml) at room temperature. The solution wasstirred at room temperature for 24 hours. After the reaction, thesolvent was stripped and the residue was stirred in ether (200 ml). Theinsolubles were removed by filtration. The oily residue fromconcentration of the ether solution was purified by two flashchromatography (SiO₂, 75 g; eluted with dichloromethane, DCM, and 1-2%C;H₃OH in DCM) and SiO₂, 100 g; eluted with DCM, 1 l; and 1% C;H₃OH inDCM, 1.2 l). Two close compounds were separated. The lower compound onTLC 3.66 g) was treated with HCl/ether in ethanol, and the solid saltwas precipitated with hexane. Recrystallization from ethanol andisopropyl ether yielded white crystals 3.26 g, m.p. 210°-214° C. dec.

ANALYSIS: Calculated for C₂₄H₂₄FN₃O₃•HCl: 62.95% C; 5.50% H; 9.18% N;Found: 62.70% C; 5.58% H; 9.13% N

EXAMPLE 2274-Fluoro-N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimidemaleate (A)1-Benzoyl-6-fluoro-3-(1-phenoxycarbonyl-4-piperidinyl)-1H-indazole

To a solution of1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole (2.0 g, 5.93mmol) in dichloromethane (100 ml) was added phenyl chloroformate (3.9ml, 29.65 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 24 hours, refluxed for an additional 0.5 hours andsubsequently concentrated. The remaining residue was dissolved intodichloromethane and washed with 10% H;Cl (aq.). The organic phase wasdried (MgSO₄), filtered, and concentrated to give an oil which waspurified via flash column chromatography (silica gel, 20% DCM/EtOAc).Concentration of the product-containing fractions gave an oil whichsolidified on standing. The white solid was washed with EtOAc, leaving0.47 g of the desired product, m.p. 137°-139° C.

ANSLYSIS: Calculated for C₂₆H₂₂FN₃O₃: 70.42% C; 5.00% H; 9.48% N; Found:70.38% C; 4.81% H; 9.42% N

(B) [4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]acetronitrile

To a suspension of1-benzoyl-6-fluoro-3-(1-phenoxycarbonyl-4-piperidinyl)-1H-indazole (31.6g, 71.3 mmol) in ethanol (500 ml) was added ,50% KOH(aq.) (100 g of KOHin 100 g H₂O) at room temperature. The reaction mixture was warmed toreflux for 4 hours and cooled to room temperature. After adjusting thepH to about one (to litmus) using HCl (con., 110 ml, the volatiles wereremoved under reduced pressure. The remaining wet solid was diluted withwater and collected via filtration. The solid material was dissolvedinto hot water to which 50% N;aOH(aq.) was added (pH was about 10, tolitmus). The precipitated 4-(6-fluoro-1H-indazol-3-yl)piperidine (10.7g) was filtered and used without further purification.

To a stirred suspension of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.95g, 22.6 mmol) and NaHCO₃ (2.1 g, 24.9 mmol) in dry acetonitrile (110 ml)was added chloroacetonitrile (1.6 ml, 24.9 mmol) at room temperature,under nitrogen. The suspension was warmed to reflux for 22.5 hours,cooled to room temperature, and subsequently filtered. The reaminingsolids were washed with DCM and the ciombined filtrates wereconcentrated. The resulting brown oil was dissolved into EtOAc andwashed with water. The organic phase was dried (MgSO₄), filtered andconcentrated to give a brown solid which was re-dissolved into DCM/EtOAcand flushed through alumina with DCM. The eluent was concentrated togive 5.2 g of the desired product as a solid, m.p. 149°-151° C.

ANALYSIS: Calculated for C₁₄H₁₅FN₄; 65.10% C; 5.85% H; 21.69% N; Found:64.84% C; 5.90% H; 21.74% N

(C). 2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]ethylamine

To a solution of[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]-acetronitrile (6.1 g, 23.6mmol) in dry THF (235 ml) was added (dropwise) lithium aluminum hydride(LAH) (28.4 mmol, 1.0M in THF) at room temperature, under nitrogen. Uponcomplete addition, the reaction mixture was warmed to reflux for 3hours. After cooling to 0 C. in an ice bath, the reaction was carefullyquenched with water (4.0 ml). The solids were removed via filtration andwashed with THF. The combined filtrates were concentrated to give 5.6 gof the desired product. This material was suspended in DCM and filteredto give the product as an off-white solid, m.p. 125°-128° C.

ANALYSIS: Calculated for C₁₄H₁₉FN₄; 64.10% C; 7.30% H; 21.36% N; Found:63.60% C; 7.10% H; 21.03% N

(D).4-Fluoro-N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimidemaleate

To a solution of 2-[4-(6-fluoro-1H-3-indazolyl)-1-piperidinyl]ethylamine(6.1 g, 23.3 mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride(4.2 g, 25.5 mmol) at room temperature under nitrogen. The reactionmixture was warmed to 80 C. for 2.5 hours at which time it was allowedto cool to room temperature. The DMF was removed under reduced pressureto give a brown oil which was dissolved into DCM/MeOH. Purification viaflash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g ofthe desired product as a white solid. The maleate salt was prepared inmethanol (75 ml) using maleic acid (2.1 eq.). The precipitated salt wascollected via filtration and recrystallized from acetronitrile to give awhite solid, m.p. 193°-195° C.

ANALYSIS: Calculated for C₂₂H₂₀F₂N₄O₂•C₄H₄O₄: 59.31% C; 4.59% H; 10.64%N; Found 59.15% C; 4.80% H; 10.80% N

EXAMPLE 228N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-3-methylphthalimidehydrochloride

A solution of 3-[4-[(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethylamine(5.9 g, 22.4 mmol), 3-methylphthalic anhydride (3.7 g, 22.5 mmol) andDMF (120 ml) was stirred at 85° C. for 22 hours under N₂. Most of theDMF was distilled off to afford 12.5 g of a dark oil. The oil waspurified by preparative HPLC (Waters Associates Prep 500 using 2 silicagel columns and 4% MeOH—CH₂Cl₂ as eluent) to yield 6.4 g of a yellowfoam. A 1.0 g sample was suspended in MeOH (25 ml) and the mixture wasmade acidic with ethereal HCl. After about 20 minutes the resultantsolution was filtered and the filtrate was diluted with anhydrous Et₂Oto precipitate the salt. The light yellow solid was collected to give0.90 g which was triturated with boiling CH₃CN (40 ml) and after coolingthe product was collected to provide 0.75 g of a white solid, m.p.266°-269° C.

ANALYSIS: Calculated for C₂₂H₂₂FN₅O₂•HCl: 59.53% C; 5.22% H; 15.78% N;Found: 59.31% C; 4.98% H; 15.77% N

EXAMPLE 229N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]propyl]phthalimidehydrochloride

A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (7.0 g, 31.8 mmol),NaHCO₃ (2.9 g, 34.5 mmol), N-(3-bromopropyl)phthalimide (8.5 g, 31.8mmol) was acetronitrile (200 ml) was stirred at reflux under N₂ for 21hours. Most of the acetronitrile was removed in vacuo and the resultantyellow residue was triturated with H₂O to afford a solid. The productwas isolated by filtration and dried to yield 12.7 g. Recrystallizationfrom EtOH gave 7.8 g of a yellow solid. A 2.0 g sample was suspended inMeOH (25 ml) and the pH was adjusted to pH˜1 with ethereal-HCl. After 30minutes of stirring at ambient temperature, the thick suspension wasdiluted with isopropyl ether (10 ml) and Et₂O (50 ml) and the saltcollected to yield 1.9 g. Recrystallization from EtOH provided 1.4 g(38%) of a light yellow solid, m.p. 261°-264° C.

ANALYSIS: Calculated for C₂₂H₂₂FN₅O₂•HCl; 59.53% C; 5.22% H; 15.78% N;Found: 59.48% C; 5.25% H; 15.56% N

EXAMPLE 2304-Fluoro-N-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimidemaleate (A)1-Benzenesulfonyl-3-(1-phenoxycarbonyl-4-piperazinyl)-1H-indazole

To a solution of1-benzenesulfonyl-3-(1-methyl-4-piperazinyl)-1H-indazole (2.1 g, 5.89mmol) in dichloromethane (100 ml) was added phenyl chloroformate (3.8ml, 29.45 mmol) at room temperature. The reaction mixture was warmed toreflux for 2 hours, cooled to room temperature, and concentrated. Theresidue was diluted with ethyl acetate, filtered and purified via flashcolumn chromatography (silica gel, ethyl acetate). Concentration of theproduct containing fractions gave an oil which solidified on standing.The product was washed well with heptane to give 1.5 g of a white solid,m.p. 112°-114° C.

ANALYSIS: Calculated for C₂₄H₂₂N₄O₄S: 62.32% C; 4.79% H; 12.11% N;Found: 62.28% C; 4.73% H; 12.15% N

(B) [4-(1H-Indazol-3yl)-1-piperazinyl]acetronitrile

To a suspension of1-benzenesulfonyl-3-(1-phenoxycarbonyl-4-piperazinyl)-1H-indazole (31.3g, 67.7 mmol) in ethanol (500 ml) was added 50% KOH (aq.) (100 g of KOHin 100 g H₂O) at room temperature. The reaction mixture was warmed toreflux for 6.5 hours and cooled to room temperature. After adjusting thepH to about two using HCl (con., 120 ml), the volatiles were removedunder reduced pressure. The remaining residue was diluted with water andremoved via filtration. The aqueous filtrate was washed with EtOAc andbasified to pH=8 using 50% N;aOH (aq.) The product was extracted into10:1 dichloromethane/isopropylalcohol. The combined organics were dried(MgSO₄), filtered, and concentrated to give 13.0 g of desired3-piperazinl-yl-1H-indazole as a brown solid which was used withoutfurther purification.

To a stirred suspension of 3-piperazin-1-yl-1H-indazole (6.0 g, 29.7mmol) and NaHCO₃ (2.7 g, 32.7 mmol) in dry acetonitrile (125 ml) wasadded chloroacetronitrile (2.1 ml, 31.2 mmol) at room temperature, undernitrogen. The suspension was warmed to reflux for 17.5 hours, cooled toroom temperature, and subsequently filtered. The reamining solids werewashed with dichloromethane and the combined filtrates wereconcentrated. The resulting brown oil was purified via flash columnchromatography (silica gel, 0-50% EtOAc/DCM) to give 4.0 g of product asan off-white solid, m.p. 121°-123° C.

ANALYSIS: Calculated for C₁₃H₁₅N₅: 64.71% C; 6.27% H; 29.02% N; Found:64.47% C; 6.23% H; 28.82% N

(C) 4-Fluoro-N-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimidemaleate

To a solution consisting of[4-(1H-indazol-3-yl)-1-piperazinyl]acetronitrile (8.7 g, 36.1 mmol) intetrahydrofuran (360 ml) was added lithium aluminum hydride (dropwise,43.3 ml of a 1.0M solution in tetrahydrofuran, 43.3 mmol) at roomtemperature, under nitrogen. The reaction mixture was warmed to refluxfor 3 hours at which time it was allowed to cool to room temperature.The reaction was carefully quenched with water (3.5 ml) and theprecipitated salts were removed via filtration and washed with EtOAc.The combined filtrates were concentrated to give a solid. This materialwas suspended in ether (4 days) and collected via filtration to give 4.7g of 2-[4-(1-indazol-3-yl)-1-piperazinyl]ethylamine which was usedwithout further purification.

A solution of intermediate2-[4-(1-indazol-3-yl)-1-piperazinyl]ethylamine (1.0 g, 4.1 mmol) and4-fluorophthalic anhydride (0.75 g, 4.5 mmol) in dimethylformamide (40ml) was warmed to 80 C. for 4 hours. After cooling to room temperature,the dimethylforamide was removed in vacuo (<0.5 mmHg, 55 C) to give abrown oil which solidified on standing. The solid material was suspendedin EtOAc and warmed to reflux for 3 hours. The desired product remainedas a yellow solid (0.86 g) and was collected via filtration and driedunder high vacuum. The maleate salt was prepared in refluxing methanolusing maleic acid (0.53 g, 4.6 mmol). The off-white solid was collectedvia filtration and washed with methanol, m.p. 211°-215° C.

ANALYSIS: Calculated for C₂₁H₂₀FN₅O₂•C₄H₄O₄: 58.94% C; 4.75% H; 13.75%N; Found: 58.69% C; 4.91% H; 13.77% N

EXAMPLE 231N-[2-[4-(1-Decanoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimidemaleate

To a stirred suspension of NaH (0.50 g of a 60% oil dispersion, 12.5mmol) in dimethylformamide(DMF) (10 ml) under N₂ and cooled to −15 C.,was added dropwise.2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-1H-isoindol-1,3-(2H-dione(4.0 g, 10.2 mmol) dissolved in DMF (45 ml) over 45 minutes so that thetemperature did not exceed −8 C. The reaction was stirred for 1 hourallowing the temperature to warm to 0 C. The reaction was cooled to −12C and a solution of decanoyl chloride (2.9 g, 15.3 mmol) in DMF (13 ml)was added dropwise so that the temperature remained below −5 C. Aftercomplete addition, the reaction was stirred at ambient temperature for18 hours. The reaction was poured into ice-cold H₂O (125 ml) and theaqueous mixture was extracted with EtOAc. The EtOAc extract was washedwith H₂O/brine, dried with MgSO₄ and concentrated to yield 5.7 g of abeige oil that readily crystallized. This was combined with anothersample (6.4 g total) and purification via flash chromatography, oversilica gel using 3% MeOH—CH₂Cl₂ as eluent, afforded 4.9 g of a whitesolid. Another previously purified sample was combined with this (6.3 g,11.5 mmol total) and the product was dissolved in hot absolute ethanol(100 ml). Maleic acid (1.4 g, 12.1 mmol) was added and the solution wasstirred at a mild reflux for 30 minutes. The reaction was concentratedto a white slush that was diluted with petroleum ether (100 ml) andstirred for 2 hours. The resultant solid was collected to yield 5.5 g ofshiny white crystals. The salt was recrystallized twice from absoluteethanol to afford 4.3 g and a third recrystallization from CH₃CN gave3.8 g of the maleate salt as a white solid, m.p. 154°-156° C.

ANALYSIS: Calculated for C₃₁H₃₈FN₅O₃•C₄H₄O₄: 63.34% C; 6.38% H; 10.55%N; Found: 63.46% C; 6.33% H; 10.60% N

EXAMPLE 232N-2-4-(1-Benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimidehydrochloride

A mixture of2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-1H-isoindol-1,3-(2H)-dione(6.0 g, 15 mmol) and benzoyl chloride (25 ml) was stirred at 175 C underN₂ for 2.0 hours. The reaction was cooled and diluted with anhydrousEt₂O) and the resultant hydrochloride salt was collected to yield 7.2 g.The compound was stirred in boiling absolute ethanol (300 ml) for 1 hourand then at ambient temperature overnight. The solid was collected anddried to afford 6.9 g. Recrystallization from MeOH gave 3.9 g of a lightgrey solid, m.p. 257°-260° C.

ANALYSIS: Calculated for C₂₈H₂₄FN₅O₃•HCl: 62.98% C; 4.72% H; 13.12% N;Found: 62.92% C; 4.70% H; 13.22% N

EXAMPLE 233N[2-[4-(1-Ethoxycarbonyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimidemaleate

A mixture ofN-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (1.8g, 4.6 mmol) and ethyl chloroformate (5.7 g, 52.3 mmol) was heated on astream bath for 10 minutes. The reaction was cooled and an additional2.3 g (20.9 mmol) ethyl chloroformate was added. The reaction wasreturned to the steam bath for 10 minutes longer and then cooled. Theresultant solid was triturated with anhydrous Et₂O and collected toyield 2.0 g. The solid was suspended in H₂O (100 ml) and NaHCO₃ wasadded to make the pH≈8. The aqueous mixture was extracted with CH₂Cl₂and the CH₂Cl₂ extract was washed with H₂O, dried with Na₂SO₄ andconcentrated to afford 2.0 g of a yellow oil that crystallized readily.The product was flashed over 80 g silica gel using 2% Et₂NH-EtOAc aseluent to afford 1.10 g (2.36 mmol) of an off-white solid. The compoundwas dissolved in hot absolute ethanol (55 ml) and maleic acid (0.28 g,2.36 mmol) was added. The solution was refluxed gently for 10 minutesand then cooled. Most of the ethanol was removed in vacuo and theresultant white suspension was diluted with anhydrous Et₂O (50 ml). Thesolid that was produced was collected to yield 1.35 g. Recrystallizationfrom CH₃CN gave 1.15 g of the maleate salt as a white powder, m.p.214°-216° C.

ANALYSIS: Calculated for C₂₄H₂₄FN₅O₄•C₄H₄O₄: 57.83% C; 4.85% H; 12.04%N; Found: 57.87% C; 4.96% H; 11.98% N

EXAMPLE 2343-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-3H-quinazolin-4-one

A stirred mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (4 g, 18.2mmol), K₂CO₃ (3.76 g, 27.2 mmol) and3-(2-chloroethyl)-2-methyl-3H-4-quinazolinone (6.0 g, 27 mmol) inacetronitrile (300 ml) was heated at reflux for 16 hours. The reactionwas complete as judged by TLC. The solids were filtered and the solventwas evaporated. The residue was purified over a flash chromatographycolumn (SiO₂, 75 gm, eluted with dichloromethane and MeOH indichloromethane). The pure product thus obtained weighed 6.5 gm.Recrystallization from ethanol yielded white crystals, 3.94 gm (53%),m.p. 164°-165° C. This material appeared pure by TLC over silica gelplates.

ANALYSIS: Calculated for C₂₃H₂₃FN₄O₂: 67.97% C; 5.70% H; 13.78% N:Found: 67.66% C; 5.66% H; 13.60% N

EXAMPLE 2354-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-[3-(2,3-dihydro-1-isoindol-2-yl)propyl]piperidinedifumarate

A stirred mixture of3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46g, 12.5 mmol), K₂CO₃ (4 g, 29 mmol) and α,α′-clibromo-o-xylene (3.3 g,2.5 mmol) in acetronitrile (300 ml) was heated at reflux for 3.5 hours.The mixture was cooled and the insolubles were filtered. The dark redsolution was concentrated down to a dark oil. This oil was purified byflash chromatography over a silica gel column (SiO₂, 45 g; eluted withdichloromethane and MeOH in dichloromethane). The product thus obtainedweighed 1.95 g as an oil. This oil was dissolved in ethanol and wastreated with a solution of fumaric acid (600 mg) in ethanol. theresulting crystals were collected as an off white solid and weighed 1.44gm, m.p. 206°-209° C.

ANALYSIS: Calculated for C₂₃H₂₆FN₃O•2C₄H₄O₄: 60.88% C; 5.60% H; 6.87% N;Found: 60.47% C; 5.81% H; 6.84% N

EXAMPLE 2364-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]piperidinedihydrochloride

A mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.67 g,10.1 mmol), α,α′-dibromo-o-xylene (2.76 g, 10.4 mmol) and K₂CO₃ (3.2 g,23 mmol) in acetonitrile (300 ml) was heated at reflux for 1 hour. Themixture turned pinkish and reaction was complete. The mixture wascooled, then filtered. The solution was concentrated down to a foam.Extraction was ether yielded 1.13 g of off-white solids. This materialwas dissolved into methanol with another batch (1.15 g), prepared in asimilar way, and was treated with ethereal HCl-ether (15 ml, 1M). Thecrystals which formed weighed 2.35 g, with m.p.=259°-262° C.

ANALYSIS: Calculated for C₂₂H₂₄FN₃O₂•2HCl; 60.28% C; 5.98% H; 9.59% N;Found: 59.98% C; 5.83% H; 9.48% N

EXAMPLE 2374-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-[2-(5-fluoro-2,3-dihydro-1H-isoindol-2-yl)ethyl]piperidinedifumarate

To a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-4-fluorophthalimide(4.5 g, 10.9 mmol) in tetrahydrofuran (120 ml) was charged with asolution of lithium aluminum hydride (35 ml, 35 mmol, 1M in ether)dropwise under N₂ at room temperature. The mixture was stirred at roomtemperature for 24 hours. The excess of hydride was quenched carefullywith ice chips and 5 ml of 20% N;aOH. The mixture was stirred for 1hour, diluted with EtOA (200 ml) then filtered. The organic solution wasconcentrated to dryness. The residue was purified by flashchromatography over a silica gel column (SiO₂, 70 gin; eluted with 1%CHaOH: 99% dichloromethane). The product thus obtained (weighed ˜3.0 g)was dissolved into ethanol and treated with a solution of fumaric acid(918 mg) in ethanol. The crystals formed were collected to yield 2.25 gof white crystals, m.p. 228°-229° C.

ANALYSIS: Calculated for C₂₂H₂₃F₂N₃O•2C₄H₄O₄: 58.53% C; 5.08% H; 6.83%N; Found: 58.478% C; 4.98% H; 6.78% N

EXAMPLE 2384-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)propyl]piperidinefumarate

A stirred mixture of2-[4-(6-fluoro-1,2-benziosoxazol-3-yl)-1-piperidinyl]propylamine (2.92g, 10.5 mmol), α,α′-dibromo-o-xylene (3.0 g, 11.03 mmol) and K₂CO₃ (3.5g, 25.3 mmol) in acetronitrile (150 ml) was heated at reflux for hours.The insolubles were filtered off. The solvent was removed on a rotaryevaporator. The residue was purified twice by flash chromatography overa silica gel column (40 g and 45 g of silica gel). The product afterpurification weighed 1.15 g. This oil was treated with a solution offumaric acid (490 mg) in ethanol. The off white crystals were collectedto yield 680 mg, m.p. 164°-165° C.

ANALYSIS: Calculated for C₂₃H₂₆FN₃O•C₄H₄O₄: 65.44% C; 6.10% H; 8.48% N;Found: 64.83% C; 6.01% H; 8.08% N

EXAMPLE 239N-[3-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propoxy]-2,3-dihydro-1H-isoindoledihydrochloride

To a stirred mixture of1-(3-amino-2-hydroxypropyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine(2.24 g, 7.6 mmol), K₂CO₃ (1.61 g, 11.7 mmol) in acetonitrile (100 ml)was added α,α′-dibromo-o-xylene (1.54 g, 6.1 mmol). The mixture washeated at reflux for 4 hours then cooled. The insolubles were filtered.The dark red solution was concentrated down. The residue was purified byflash chromatography over s silica gel column (SiO₂, 30 g; eluted with1% C;H₃OH in dichloromethane). The product so Obtained weighed 940 mg asan oil. This oil was dissolved in ethanol and was treated with asolution of HCl in ethanol (188 mg of AcCl in ethanol). The dark solidswere collected and recrystallized again in ethanol to yield off-whitecrystals (1.01 g), m.p. 240°-243° C.

ANALYSIS: Calculated for C₂₃H₂₆FN₃O₂•2HCl: 58.98% C; 6.03% H; 8.97% N;Found: 58.72% C; 6.16% H; 8.94% N

EXAMPLE 240N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-5-(triisopropylsilyl)oxy-1H-isoindoledifumarate

A mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (1.52 g,5.73 mmol), 1,2-dibromo-4-(triisopropylsilyl)oxy-xylene (2.4 g, 5.7mmol) and K₂CO₃ (1.8 g, 13 mmol) in acetronitrile (300 ml) was stirredovernight (18 hours) at room temperature. The mixture was filtered andthe solvent was stripped. The residue was purified by flashchromatography over a silica gel column (7 gm of SiO₂; eluted with 1-3%C;H₃OH in dichloromethane. The product thus purified (weight: 900 mg)was converted to the fumarate salt by treatment with fumaric acid (194mg) in hot ethanol. The crystals were collected and weighed 590 mg, m.p.208°-210° C.

ANALYSIS: Calculated for C₃₁H₄₄FN₃O₂Si•2C₄H₄O₄: 60.84% C; 6.81% H; 5.46%N; Found: 60.41% C; 6.87% H; 5.35% N

EXAMPLE 241N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-5-hydroxy-1H-isoindolefumarate hydrate

To a stirred solution ofN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-5-(triisopropylsilyl)oxy-1H-isoindole(11.5 g, 21.5 mmol) in tetrahydrofuran (50 ml) was added a solution oftetrabutyl ammonium fluoride (1M in tetrahydrofuran, 24 ml, 24 mmol) inportions at room temperature. The mixture was stirred for 2 hours, thendiluted with methylene chloride (200 ml). The organics was washed withH₂O and brine, dried with anhydrous MgSO₄. The solvents were removed andthe residue was purified by flash chromatography over a silica gelcolumn (90 g of SiO₂; eluted with 1-4% of CH₃OH in methylene chloride).The desired fractions were combined and concentrated to give 1.5 g offree base. This solid was recrystallized from ethanol to yield 570 mg ofoff white crystals. The crystals were converted to fumarate salt in hotethanol and water to give pinkish crystals, 560 mg, m.p. 191°-193° C.

ANALYSIS: Calculated for C₂₂H₂₄FN₃O₂•C₄H₄O₄•H₂O: 60.57% C; 5.87% H;8.15% N; Found: 60.20% C; 5.73% H; 8.04% N

EXAMPLE 2424-(6-Fluoro-1H-indazol-3yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]piperidinedimaleate

To a solution ofN-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimidehydrochloride (Example 183) (3.1 g, 7.91 mmol) in THF (100 ml) was addedlithium aluminum hydride (16.6 ml of a 1.0M solution in THF, 16.6 mmol)at room temperature, under nitrogen. The reaction mixture was warmed toreflux for 6.5 hours and cooled to room temperature. The reaction wasquenched with water (1.5 ml, dropwise) and the precipitated salts wereremoved via filtration. The solids were washed with DCM and the combinedfiltrates concentrated to give 2.5 g of the crude product as a solid.The dimaleate salt was prepared in methanol using 3.5 g (>4.0 e.q.) ofmaleic acid. The light green precipitate was collected via filtrationand washed with methanol. Recrystallization from methanol gave 2.1 g ofthe desired product as an off-white solid, m.p. 196°-199° C.

ANALYSIS: Calculated for C₂₂H₂₅FN₄•2C₄H₄O₄: 60.40% C; 5.58% H; 9.39% N;Found: 60.33% C; 5.42% H; 9.42% N

EXAMPLE 2432-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(2,3-dihydro-1H-isoindol-2-yl)ethanone(A) 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide

The mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (6.77 g,30.7 mmol), K₂CO₃ (5 g, 36.2 mmol) and 2-bromoacetamide (4.46 g, 32.3mmol) in acetrontrile (250 ml) was heated to reflux for 4 hours. Theinsolubles were filtered and rinsed with dichloromethane (DCM). Thesolvents were removed. The residual solid was dissolved in DCM and uponconcentration of this solution, 2.3 g of product crystallized out andwas collected when the volume was reduced to about 50 ml. The rest ofthe product in DCM was purified by flash chromatography over a silicagel column (80 gm, SiO₂; eluted with DCM and 1% C;H₃OH in DCM). Thetotal product (4.2 g) thus purified was recrystallized from ethanol toyield 2.82 g of white crystals, m.p. 170°-172° C. dec.

ANALYSIS: Calculated for C₁₄H₁₆FN₃O₂: 60.64% C; 5.82% H; 15.15% N;Found: 60.66% C; 5.87% H; 15.10% N

(B)2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(2,3-dihydro-1H-isoindol-2-yl)-ethanone

To a mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g,9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% inoil, 20.1 mmol) at room temperature under N₂. The mixture was heated to65 C for 3 hours. α,α′-dibromoxylene (2.43 g, 9.2 mmol) was added andthe resulting mixture was heated at 70 C. for 4 hours, then leftstanding overnight for 16 hours. The DMF mixture was poured into H₂O(400 ml) and the organics were extracted into ethyl acetate (250 ml).The ethyl acetate solution was washed with brine and dried over MgSO₄.The solvent was removed and the residue was purified by flashchromatography over a silica gel column (SiO₂, 45 gm; eluted with 1%C;H₃OH: 99% DCM). The product thus purified as a white solid weighed1.73 g. Recrystallization from a small amount of ethanol yielded whitecrystals: 1.65 g, m.p. 184°-185° C.

ANALYSIS: Calculated for C₂₂H₂₂FN₃O₂: 69.64% C; 5.84% H; 11.07% N;Found: 69.48% C; 5.67% H; 11.05% N

EXAMPLE 2442-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(2,3-dihydro-1H-isoindol-2-yl)ethanonefumarate

Free base (1 g, Example 243B) of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(2,3-dihydro-1H-isoindol-2-yl)ethanonedissolved in hot ethanol (˜10 ml) was treated with a solution of fumaricacid (306 mg) in hot ethanol. The mixture was cooled and the productcollected, 1.2 gm, m.p. 223°-225° C.

ANALYSIS: Calculated for C₂₂H₂₂FN₃O₂•C₄H₄O₄: 63.02% C; 5.29% H; 8.48% N;Found: 62.86% C; 5.03% H; 8.39% N

EXAMPLE 2454-(6-Fluoro-1H-indazol-3-yl)-1-[2-(5-fluoro-2,3-dihydro-1-H-isoindol-2-yl)ethyl]piperidinedimaleate

To a solution consisting of2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethylamine (6.1 g, 23.2mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5mmol) at room temperature, under nitrogen. Then reaction mixture waswarmed to 80 C. for 2.5 hours at which time it was allowed to cool toroom temperature. The DMF was removed under reduced pressure (<0.5 mmHg,55 C.) to give a brown oil which was dissolved into DCM/MeOH.Purification via flash column chromatography (silica gel, 2% MeOH/DCM)afforded 3.6 g of4-fluoro-N-[2-[4(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimide.To a solution of the latter compound (3.6 g 8.8 mmol) in anhydrous THF(100 ml) was added LAH (18.4 ml of a 1.0M solution in THF, 18.4 mmol) atroom temperature, under nitrogen. The reaction mixture was warmed toreflux for 4 hours. Upon cooling to room temperature, the reaction wasquenched with water (1.5 ml, dropwise). The precipitated salts wereremoved via filtration and washed with DCM. The combined filtrates wereconcentrated to give a solid which was purified via flash columnchromatography (silica gel, 0-8% MeOH/DCM). The product containingfractions were concentrated to give 2.4 g product as an off-white solid.The dimaleate salt was prepared in methanol using 2.4 eq. of maleicacid. The white precipitate was collected via filtration and washed withmethanol, m.p. 186°-188° C.

ANALYSIS: Calculated for C₂₂H₂₄F₂N₄•2C₄H₄O₄: 58.63% C; 5.25% H; 9.12% N;Found: 58.45% C; 5.29% H; 9.07% N

EXAMPLE 2464-(1H-Indazol-3-yl)-1-[2-(2,3-dihydro-5-fluoro-1H-isoindol-2-yl)ethyl]piperazinedimaleate

To a suspension consisting of4-fluoro-2-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (4.8g, 12.1 mmol) in THF (20 ml) was added LAH (dropwise, 25.5 ml of a 1.0Msolution in THF, 25.5 mmol) at room temperature, under nitrogen. Thereaction mixture was warmed to reflux for 4 hours during which time itbecame homogeneous. Upon cooling to room temperature, the reaction wascarefully quenched with water (11.5 ml) and the precipitated salts wereremoved via filtration and washed with DCM. The combined filtrates wereconcentrated to give the crude product. This material was dissolved inDCM/MeOH (minimal) and purified via preparative HPLC (single column ofsilica gel, 5% MeOH/DCM, 4 L, then increased to 10% MeOH/DCM, 3 L) togive 2.9 g of the desired product. The dimaleate salt was prepared inmethanol (200 ml using maleic acid (2.2 eq., 2.0 g, 17.5 mmol). Theresulting salt was collected via filtration and washed with methanol togive an off-white solid, m.p. 182°-184° C.

ANALYSIS: Calculated for C₂₁H₂₄FN₅•2C₄H₄O₄: 58.29% C; 5.40% H; 11.72% N;Found: 57.96% C; 5.39% H; 11.65% N

EXAMPLE 2474-(6-Fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-4-methyl-1H-idoindol-2-yl)ethyl]piperazinedifumarate

To a stirred solution of2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-3-methylphthalimide(5.4 g, 13.3 mmol) in THF (200 ml) under N₂ was added, dropwise, LAH(30.0 ml of a 1.0M LAH/THF solution). After complete addition, thereaction was stirred at reflux for 4.5 hours. The reaction was cooled inan ice bath and (2 ml) was carefully added followed by 1.0M NaOH (3 ml).The mixture was filtered and the filtrate was concentrated to yield 5.0g of a brown oil. Trituration of the oil with Et₂O produced a whitesolid that was isolated by filtration to give 2.1 g of a white solid.The compound was purified via preparative HPLC (Water's Associates PrepLC/500 using 2 silica gel columns and eluting initially with 10%MeOH—CH₂Cl₂ changing to 15% MeOH—CH₂Cl₂). Concentration of appropriatefractions yielded 1.5 g (4.0 mmol) of a beige solid. The compound wasdissolved in EtOAc (125 ml) and MeOH (4 ml) and the solution was warmedand filtered. The filtrate was stirred near reflux and a solution offumaric acid (0.92 g, 8.0 mmol) in hot MeOH-EtOAc (1:1, 8 ml) was added.The mixture was allowed to cool and the resultant product was collectedto give 2.1 g of an off-white solid, m.p. 212°-215° C.

ANALYSIS: Calculated for C₂₂H₂₆FN₅•2C₄H₄O₄: 58.91% C; 5.60% H; 11.45% N;Found: 58.88% C; 5.66% H; 11.62% N

EXAMPLE 2484-(6-Fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-5-methyl-1H-isoindol-2-yl)ethyl]piperazinedifumarate

To a stirred solution of2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-4-methylphthalimide(5.46, 13.3 mmol) in THF (200 ml) under N₂ was added, dropwise, LAH(30.0 ml of a 1.0M LAH/THF solution). After complete addition, thereaction was stirred at reflux for 4.5 hours. The reaction mixture wascooled in an ice bath and H₂O (2 ml) was carefully added followed by1.0M NaOH (3 ml). The mixture was filtered and the filtrate wasconcentrated to yield 4.7 g of a brown solid. The compound wastriturated with Et₂O and filtered to give 2.4 g of a white solid. Thecompound was purified by preparative HPLC (Water's Associates Prep 500using 2 silica gel columns and eluting initially with 10% MeOH—CH₂Cl₂switching to 15% MeOH—CH₂Cl₂). Concentration of appropriate fractionsgave 1.7 g (4.5 mmol) of a beige solid. The solid was dissolved in EtOAc(130 ml) and MeOH (4 ml) and filtered. The filtrate was stirred nearreflux and was treated with a solution of fumaric acid (1.04 g, 9.0mmol) dissolved in hot MeOH (6 ml) and EtOAc (6 ml). The mixture wascooled to ambient temperature and the salt was isolated by filtration toprovide 2.4 g of an off-white solid, m.p. 212°-215° C.

ANALYSIS: Calculated for C₂₂H₂₆FN₅•2C₄H₄O₄: 58.91% C; 5.60% H; 11.45% N;Found: 58.63% C; 5.35% H; 11.41% N

EXAMPLE 249

4-(6-Fluoro-1H-indazol-3-yl)-1-[2-(5-fluoro-2,3-dihydro-1H-isoindol-2-yl)ethyl]piperazinedimaleate

To a stirred solution of2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-4-fluorophthalimide(2.9 g, 7.1 mmol) in THF (100 ml) under N₂ was added, dropwise, LAH(16.0 ml of a 1.0M LAH/THF solution) over 30 minutes. The reaction wasstirred at ambient temperature for 1 hour, reflux for 3.5 hours and thenat ambient for 18 hours. The reaction was cooled in an ice bath and H₂O(2 ml) was carefully added followed by 1.0M NaOH (2 ml). The mixture wasfiltered and the filtrate cake was rinsed with 10% MeOH—EtOAc. Thefiltrate was concentrated to yield 2.5 g of a beige solid. The compoundwas purified by preparative HPLC (Waters Associates Prep 500 using 2silica gel columns and eluting initially with 8% MeOH—CH₂Cl₂ increasingthe polarity to 12% MeOH—CH₂Cl₂) to yield 1.7 g (4.3 mmol) of a greysolid. The compound was dissolved in warm EtOAc (75 ml) and MeOH (7 ml)and filtered. The filtrate was warmed and stirred and maleic acid (1.0g, 8.6 mmol) was added. The reaction was stirred at gentle reflux for 15minutes and then at ambient temperature for 45 minutes. Anhydrous Et₂O(100 ml) was added and the solid was collected to give 2.5 g.Recrystallization from CH₃CN provided 1.7 g of the dimaleate salt as alight grey solid, m.p. 196°-199° C.

ANALYSIS: Calculated for C₂₁H₂₃F₂N₅•2C₄H₄O₄: 56.58% C; 5.08% H; 11.38%N; Found 56.38% C; 5.01% H; 11.38% N

EXAMPLE 2504-(1H-Indazol-3-yl)-1-[2-(2,3-dihdyro-1H-isoindol-2-yl)ethyl]piperazinedimaleate

A suspension of 4-(1H-indazol-3-yl)piperazine (1.6 g, 7.9 mmol),N-(2-bromoethyl)phthalimide (2.1 g, 7.9 mmol), and sodium bicarbonate(0.7 g, 8.3 mmol) in acetronitrile (160 ml) was warmed to reflux for 24hours. Upon cooling to room temperature, the reaction mixture wasfiltered through a pad of celite and the solids were washed with DCM.The combined filtrates were concentrated to give theN-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide which was usedwithout further purification.

To a suspension consisting ofN-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide 2.9 g, 7.9mmol) in THF (100 ml) was added LAH (dropwise, 19.0 ml of a 1.0Msolution in THF, 19.0 mmol) at room temperature, under nitrogen. Thereaction mixture was warmed to reflux for 4 hours during which time itbecame homogeneous. Upon cooling to room temperature, the reaction wascarefully quenched with water (1.5 ml) and the precipitated salts wereremoved via filtration and washed with DCM. The combined filtrates wereconcentrated to give the crude product as an oil. Purification via flashchromatography (silica gel, 5% MeOH/DCM) afforded 0.77 g of the desiredproduct. The dimaleate salt was prepared in methanol using maleic acid(2.1 eq., 0.54 G). The resulting salt was collected via filtration andwashed with methanol to give a greenish solid, m.p. 178°-183° C.

ANALYSIS: Calculated for C₂₁H₂₅N₅•2C₄H₄O₄: 60.10% C; 5.74% H; 12.08% N;Found: 59.82% C; 5.65% H; 12.10% N

EXAMPLE 2514-(6-Fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]piperazinedimaleate

To a stirred solution ofN-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (5.5g, 14.0 mmol) in THF (125 ml) under N₂ at ambient temperature was added,dropwise, LAH (33.0 ml of a 1.0M LAH/THF solution) over 30 minutes.After complete addition the reaction was stirred at ambient temperaturefor 45 minutes, and then at reflux for 4.5 hours. After stirring atambient temperature for 64 hours, the reaction was cooled in an ice bathand H₂O (5.0 ml) was carefully added followed by 1M NaOH (2 ml). Thereaction was filtered and the oily filter cake was rinsed with THF and10% MeOH-EtOAc. The combined organic filtrate was concentrated to afford5.5 g of a sticky white substance. This was combined with an additionalsample (7.5 g total) and purification via preparative HPLC (Water'sAssociates Prep LC/500 using 2 silica gel columns and 10% MeOH—CH₂Cl₂ aseluent) provided 6.0 g (16.4 mmol) of a beige solid. The product wasdissolved in warm EtOAc (150 ml) and treated with Darco-G60 for 20minutes. The decolorizing carbon as removed by filtration through a bedof celite and the warm filtrate was treated with a solution of maleicacid (3.8 g, 32.8 mmol) in hot EtOH (17 ml). A white solid precipitatedand the mixture was stirred 1.5 hours at ambient temperature. Thecompound was isolated by filtration to afford 8.9 g of a light greysolid. Recystallization from MeOH gave 5.2 g of the dimaleate salt, m.p.205°-207° C.

ANALYSIS: Calculated for C₂₁H₂₄FN₅•2C₄H₄O₄: 58.29% C; 5.40% H; 11.72% N;Found: 58.27% C; 5.31% H; 11.69% N

EXAMPLE 2526-Fluoro-3-[4-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]-1-piperazinyl]-N-phenyl-1H-indazole-1-carboxamidedimaleate

To a stirred suspension of NaH (0.40 g of 60% oil dispersion; 10.0 mmol)in DMF (10 ml) under N₂ and cooled to −3 C., was added, dropwise, asolution of4-(6-fluoro-1H-indazol-3-yl)-1-[2,3-dihydro-1H-isoindol-2-yl)ethyl]piperazine(3.3 g, 9.0 mmol) in DMF (45 ml) over 60 minutes, maintaining thetemperature below 0 C. The mixture was stirred for 60 minutes at 0 C.and then a solution of phenyl isocyanate (1.2 g, 10.0 mmol) in DMF (5ml) was added dropwise at −2 C. After complete addition the reaction wasstirred at room temperature for 20 hours. The reaction was poured intoH₂O, and the aqueous mixture was extracted with ethyl acetate. The ethylacetate extract was washed with H₂O, washed with brine, dried withMgSO₄, and concentrated to afford 5.6 g of a dark oil. The oil waspurified by preparative HPLC (Waters Associates Prep 500 using 2 silicagel columns and 4% MeOH—CH₂Cl₂ as eluent) to yield 2.9 g of a dark oil.A 2.7 g (5.6 mmol) sample was dissolved in warm EtOAc (100 ml) and MeOH(5 ml) and the particulate matter was filtered away. The filtrate waswarmed and stirred and a solution of maleic acid (1.3 g, 11.2 mmol) inhot MeOH (5 ml) was added. The reaction was refluxed mildly for 15minutes and then was stirred at ambient temperature for 2 hours. Theresultant suspension was diluted with petroleum ether (150 ml) and thedark solid collected to yield 3.2 g. The compound was recrystallizedfrom CH₃CN (utilizing Darco G-60 decolorizing carbon) to afford 1.6 g ofa grey solid, m.p. 189°-191° C.

ANALYSIS: Calculated for C₂₈H₂₉FN₆O•2C₄H₄O₄: 60.33% C; 5.20% H; 11.73%N; Found: 60.36% C; 4.86% H; 11.85% N

EXAMPLE 2534-(1-Decanoyl-6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2,yl)ethyl]piperazinedimaleate

To a stirred suspension of NaH (0.40 g of 60% oil dispersion, 10.0 mmol)in DMF (10 ml) under N₂ and cooled to −3 C. was added, dropwise, asolution of4-(6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]piperazine(3.3 g, 9.0 mmol) in DMF (45 ml) over 65 minutes so that the temperaturewas maintained below 0 C. The reaction was stirred for 1 hour and wascooled to −2 C. A solution of decanoyl chloride (1.9 g, 10.0 mmol) inDMF (5 ml) was added dropwise over 10 minutes. After complete additionthe reaction was stirred at ambient temperature for 20 hours. Thereaction was poured into H₂O (75 ml) and the aqueous mixture wasextracted with EtOAc. The EtOAc extract was washed with H₂O, washed withbrine, dried with MgSO₄ and concentrated to afford 5.1 g of a dark oil.The oil was purified by preparative HPLC (Water's Prep 2000 utilizing 1silica gel column and 4% MeOH—CH₂Cl₂ as eluent) to yield 3.1 g (66%) ofa dark oil. The oil (2.75 g, 5.3 mmol) was dissolved in warm EtOAc (100ml) was treated with maleic acid (1.26 g, 10.9 mmol). After warming for30 minutes the grey suspension was stirred at ambient temperature for 60minutes. The reaction was diluted with anhydrous Et₂O (30 ml) andpetroleum ether (200 ml) and the resultant dark grey solid was collectedto yield 3.77 g. The salt was recrystallized from CH₃CN (using DarcoG-60) to yield 2.6 g of a light grey solid, m.p. 191°-194° C.

ANALYSIS: Calculated for C₃₁H₄₂FN₅O•2C₄H₄O₄: 62.30% C; 6.70% H; 9.31% N;Found: 62.34% C; 6.74% H; 9.23% N

EXAMPLE 2544-(6-Fluoro-1H-indazol-3-yl)-1-[3-2,3-dihydro-1H-isoindol-2-yl)propyl]piperazinedimaleate

To a stirred solution of2-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propyl]phthalimide (5.3g, 13.0 mmol) in THF (200 ml) under N₂ was added, dropwise, LAH (27.0 mlof a 1.0M LAH/THF solution). After complete addition, the reaction wasstirred at reflux for 4.5 hours. The reaction was cooled in an ice bathand H₂O (2 ml) was carefully added, followed by 1.0M NaOH (3 ml). Themixture was filtered and the filtrate was concentrated to afford 4.8 gof a white solid. The compound was purified by preparative HPLC (Water'sAssociates Prep 500, utilizing 2 silica gel columns and 5% Et₂NH-EtOAcas eluent) to give 3.0 g of a beige solid. Recrystallization from EtOAcprovided 1.1 g (2.9 mmol) of an off white solid. The compound wasdissolved in hot EtOAc (200 ml) and MeOH (10 ml) and maleic acid (0.68g, 5.8 mmol) was added. The reaction was warmed for 15 minutes and afterstirring at ambient temperature for 30 minutes and standing at about 4C. for 1.5 hours, the dimaleate salt was collected to yield 1.7 g of anoff-white solid, m.p. 183°-186° C.

ANALYSIS: Calculated for C₂₂H₂₆FN₅•2C₄H₄O₄: 58.91% C; 5.60% H; 11.45% N;Found: 58.92% C; 5.47% H; 11.53% N

EXAMPLE 2552-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(2,3-dihydroindol-1-yl)ethanonefumarate

A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (10 g,45.4 mmol), K₂CO₃ (7.2 g, 52.5 mmol) and N-(2-bromoacetyl)indoline (12g, 50 mmol) in acetronitrile (300 ml) was heated at reflux for 4 hours.The mixture was cooled and filtered. The solution was concentrated downuntil solid appeared. The crystals were collected: weight 12.68 g. Themother liquor was concentrated to dryness. The residues were purifiedfurther by flash chromatography to yield an additional 1.35 g. Totalyield was 14.03 g. A 2 g sample was dissolved in ethanol/methylenechloride and was treated with a solution of fumaric acid (612 mg) inethanol to yield 2.58 g, m.p. 226°-227° C.

ANALYSIS: Calculated for C₂₂H₂₂FN₃O₂•C₄H₄O₄: 63.02% C; 5.29% H; 8.48% N;Found: 62.79% C; 5.30% H; 8.40% N

EXAMPLE 2561-(1,2,3,4-Tetrahydro-1H-isoquinolin-2-yl)-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethanonehydrochloride ethanolate

A mixture of 4-(6-fluoro-1,2-benziosoxazol-3-yl)piperidine (4.33 g, 19.7mmol), K₂CO₃ (3.45 g, 25 mmol), 1.25 eq) and2-bromoacetyl-1,2,3,4-tetrahydroisoquinole (5 g, 20 mmol) inacetronitrile (200 ml) was heated at reflux for 2 hours. The reactionwas cooled and the insolubles were filtered. The solvent was removed andthe crude oil was purified by flash chromatography over a silica gelcolumn (90 g of SiO₂; eluted with DCM and 1% C;H₃OH in DCM). The oilthus purified weighed 6.41 g. A 3 g sample was dissolved into ethanol(20 ml) and was treated with 1M-HCl-ether solution (10 ml). The crystalswere collected and recrystallized twice from ethanol to yield 2.43 g ofwhite crystals as the hydrochloride ethanolate, m.p. 206°-208° C.

ANALYSIS: Calculated fir C₂₃H₂₄FNO₂•HCl•C₂H₆O: 63.08% C; 6.56% H; 8.83%N; Found: 63.24% C; 6.62% H; 8.89% N

EXAMPLE 257N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-1,2,3,4-tetrahydroisoquinolinedifumarate

To a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(1,2,3,4-tetrahydro-1H-isoquinolin-2-yl)ethanone(2.36 g, 6 mmol) in THF (40 ml) was charged lithium aluminum hydride (15ml, 1M in ether) dropwise under N₂ at room temperature. The mixture wasstirred for 3 hours at room temperature. At the end, the excess ofhydride was quenched with ice chips and 2 ml of 20% N;aOH. The mixturewas diluted with EtOAc and filtered. The solvents were removed todryness. The residue was purified by flash chromatography over a silicagel column (SiO₂, 18 g; eluted with 1% C;H₃OH in DCM). The product thusobtained weighed 1.62 g. This material was dissolved into hot ethanoland was treated with a solution of fumaric acid (490 mg) in ethanol. Themixture was cooled and the crystals were collected to yield 1.15 g, m.p.218°-220° C.

ANALYSIS: Calculated for C₂₃H₂₆FN₃O.2C₄H₄O₄: 60.88% C; 5.60% H; 6.87% N;Found: 61.00% C; 5.50% H; 6.64% N

EXAMPLE 2582-(1,2,3,4-Tetrahydro-1H-isoquinolin-2-yl)-1-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethanonefumarate (A)1-(2-Chloroacetyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine

A solution of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.4 g, 20mmol), triethylamine (2.1 g, 21 mmol) in chloroform (50 ml) was added toa solution of chloroacetyl chloride (2.5 g, 22 mmol) in chloroform (100ml) dropwise at room temperature. The mixture was stirred for 2 hours.The solution was diluted with dichloromethane (DCM, 100 ml) and thenwashed with H₂O and brine. The solvent was removed and the oily productwas purified by flash chromatography (SiO₂, 50 g; eluted with DCM and 1%C;H₃OH in DCM). The pure product was obtained as an oil, 4.2 g.Crystallization from ethanol yielded 2.2 g of white crystals, m.p.101°-102° C.

ANALYSIS: Calculated for C₁₄H₁₄ClFN₂O₂: 56.67% C; 4.76% H; 9.44% N;Found: 56.70% C; 4.75% H; 9.46% N

(B)2-(1,2,3,4-Tetrahydro-1H-isoquinolin-2-yl)-1-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethanonefumarate

A mixture of4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl-2-chloroacetamide (3.0g, 10.8 mmol), K₂CO₃ (1.5 gm, 10.8 mmol) and1,2,3,4-tetrahydroisoquinoline (1.4 g, 10.5 mmol) in acetonitrile (90ml) was heated at reflux for 4 hours. The reaction was cooled andfiltered. The solvent was removed, and the residue was purified by flashchromatography over a silica gel column (50 g of SiO₂; eluted with DCMand 1% C;H₃OH in DCM). The light yellow oil (3.28 g) thus obtained wasdissolved in ethanol and treated with a solution of fumaric acid (968mg) in ethanol. The solid crystals were collected and recrystallizedagain to give 3.18 g of off-white crystals, m.p. 188°-189° C.

ANALYSIS: Calculated for C₂₃H₂₄FN₃O₂.C₄H₄O₄: 63.65% C; 5.54% H; 8.25% N;Found: 63.42% C; 5.33% H; 8.16% N

EXAMPLE 259N-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

A mixture ofN-[3-(2,3-epoxy)propyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine(3.56 g, 12.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.06 g, 15.4mmol) in isopropyl alcohol (150 ml) was heated at reflux for 4 hours. Atthe end of the reaction, the solvent was removed. The residual oil waspurified by flash chromatography over a silica gel column (SiO₂, 45 g,eluted with 1% C;H₃OH; 99% methylene chloride). The product thuspurified as a light oil, weighed 4.15 g. The oil was treated with asolution of fumaric acid (1.98 gm, 17 mmol) in ethanol. The whitecrystals so obtained were recrystallized in a large volume of hotethanol (˜150 ml). The recrystallized crystals weighed 2.75 g, m.p.179°-181° C.

ANALYSIS: Calculated for C₂₄H₂₈FN₃O₂.2C₄H₄O₄: 59.90% C; 5.66% H; 6.55%N; Found: 60.06% C; 5.77% H; 6.36% N

EXAMPLE 2606,7-Dimethoxy-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propyl]-1,2,3,4-tetrahydroisoquinoline

A stirred mixture of1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.2 g,11.6 mmol), K₂CO₃ (2 gm, 1.25 eq) and6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.3 g, 1.25eq) in isopropyl alcohol (200 ml) was heated at reflux for 6 hours. Themixture was cooled and filtered. The solvent was removed to about 50 mland the solution was allowed to stand overnight. Crystals (0.6 g) formedand were collected. The mother liquor was concentrated to a white solid.Recrystallization twice from ethanol yielded the product (1.95 g, m.p.153°-154° C.

ANALYSIS: Calculated for C₂₆H₃₂FN₃O₄: 66.51% C; 6.87% H; 8.95% N; Found:66.51% C; 7.05% H; 8.83% N

EXAMPLE 261N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-1,2,3,4-tetrahydroisoquinolinedimaleate

To a solution of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.8 g, 18.9mmol) in CH₃CN (200 ml) was added2-bromo-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethanone (4.8 g, 18.9mmol) and sodium bicarbonate (1.9 g, 22.7 mmol) at room temperature. Thereaction mixture was warmed to reflux (4 hours), cooled to roomtemperature and filtered through a pad of celite. The solids were washedwith DCM and the combined filtrates were concentrated. The remainingresidue was purified via preparative HPLC (silica gel, 5-10% MeOH/DCM)to give 4.1 g of1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethanonewhich was used without further purification. To a suspension of thelatter (3.7 g, 9.4 mmol) in THF (100 ml) was added (dropwise) lithiumaluminum hydride (11.3 ml of 1.0M solution in THF, 11.3 mmol) at roomtemperature, under nitrogen. The reaction mixture was warmed to reflux(5 hours), cooled to room temperature and carefully quenched with water(10 ml). The precipitated salts were removed via filtration and washedwith 1:1 EtOAc/DCM. The combined filtrates were concentrated and theremaining oil was purified via flash column chromatography (silica gel,10% MeOH/DCM) to give 2.2 g of the product. The dimaleate salt wasprepared in methanol (30 ml) with maleic acid (3.0 eq.), m.p. 185°-187°C.

ANALYSIS: Calculated for C₂₃H₂₇FN₄.2C₄H₄O₄: 60.98% C; 5.78% H; 9.18% N;Found: 60.85% C; 5.75% H; 9.09% N

EXAMPLE 2622-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]-1-(1,2,3,4-tetrahydro-1H-isoquinolin-2-yl)ethanonedifumarate

A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (3.1 g, 14 mmol),2-bromoacetyl-1,2,3,4-tetrahydroisoquinoline (3.6 g, 14 mmol), NaHCO₃(1.4 g, 17 mmol) and CH₃CN (150 ml) was stirred at reflux under N₂ for 6hours. The cooled reaction was filtered and the filtrate wasconcentrated to yield 6.1 g of an off-white foam. The compound waspurified by preparative HPLC (Water's Associates prep 500 using 2 silicagel columns and 5% MeOH—CH₂Cl₂ as eluent). Concentration of appropriatefractions gave 4.1 g of an off-white solid. A 0.8 g (2.0 mmol) samplewas dissolved in warm EtOAc (30 ml) and MeOH (4 ml) was filtered. Thefiltrate was heated to reflux and was treated with a solution of fumaricacid (0.47 g, 4.0 mmol) in MeOH/EtOAc (1:1, 8 ml). The mixture wascooled and the resultant white solid was collected to yield 0.88 g. Thiswas combined with another small sample (1.0 g total) andrecrystallization from ethanol provided 0.75 g of a white solid, m.p.235°-238° C.

ANALYSIS: Calculated for C₂₂H₂₄FN₅O.2C₄H₄O₄: 57.60% C; 5.16% H; 11.19%N; Found: 57.68% C; 5.26% H; 11.31% N

EXAMPLE 263N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

To a stirred solution of2-[4-(6-fluoro-1H-indazole-3-yl)-1-piperazinyl]-1-(1,2,3,4-tetrahydro-1H-isoquinolin-2-yl)ethanone(3.2 g, 8.1 mmol) in THF (75 ml) under N₂, was added dropwise, LAH (20.0ml of a 1.0M LAH/THF solution). After complete addition, the reactionwas stirred at ambient temperature for 20 hours. The reaction was cooledin an ice bath and cold H₂O was added followed by 1 ml of 1.0M NaOH. Themixture was filtered and the filter cake was washed with EtOAc. Thefiltrate was concentrated to yield 2.5 g of a white solid. The compoundwas purified by preparatige HPLC (Water's Associates Prep 500, using 1silica gel column and 10% MeOH—CH₂Cl₂ as eluent) to yield 2.0 g of awhite solid. A 1.8 g (4.7 mmol) sample was stirred as a solution in warmEtOAc (100 ml) and was treated with a solution of fumaric acid (1.1 g,9.5 mmol) in boiling MeOH (12 ml). The reaction was warmed for 15minutes and after stirring at ambient temperature for 1.5 hours theresultant white solid was collected to yield 2.7 g of the difumaratesalt, m.p. 210°-213° C.

ANALYSIS: Calculated for C₂₂H₂₆FN₅.C₄H₄O₄: 58.91% C; 5.60% H; 11.45% N;Found: 58.77% C; 5.42% C; 11.22% N

EXAMPLE 2641-(1,2,3,4-Tetrahydro-1H-quinolin-1-yl)-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethanonefumarate

A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7g, 21.4 mmol), K₂CO₃ (3.6 g, 25.6 mmol) andN-(2-bromoacetyl)-1,2,3,4-tetrahydroquinoline (6 g, 23.6 mmol) inacetonitrile (200 ml) was heated at reflux for 1.5 hours. The mixturewas cooled and the solids were filtered off. The solvent was stripped todryness. The residue was purified by flash chromatography (SiO₂, 100 gm;eluted with methylene chloride (DCM) and 1% C;H₃OH in DCM). The productthus purified weighed 7.75 g. A sample of 1.88 g in ethanol was treatedwith a solution of fumaric acid (550 mg, 1.0 eq) in ethanol to yield thefumaric salt, 2.15 g, m.p. 162°-163° C.

ANALYSIS: Calculated for C₂₃H₂₄FN₃O₂.C₄H₄O₄: 63.65% C; 5.54% H; 8.25% N;Found: 63.52% C; 5.46% H; 8.17% N

EXAMPLE 265N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,2,3,4-tetrahydroquinolinefumarate

To a stirred solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(1,2,3,4-tetrahydroquinolin-1-yl)ethanone(5.5 g, 14 mmol) in THF (50 ml) was charged with lithium aluminumhydride (17 ml, 17 mmol, 1M in ether) dropwise under N₂ at roomtemperature. The mixture was stirred for 8 hours at room temperature. Atthe end of this period the excess of hydride was quenched with ice chipsand 3 ml of 20% NaOH. The mixture was diluted with EtOAc (150 ml) andstirred for 1 hour. The EtOAc was dried with MgSO₄ and filtered. Thesolvent was removed to dryness. The residue was purified by flashchromatography over a silica gel column (SiO₂, 55 g; eluted with 1-3%C;H₃OH: DCM). The product thus obtained weighed 1.83 g. This materialwas dissolved into hot ethanol and was treated with a solution offumaric acid (700 mg) in ethanol. The crystals were collected andweighed 1.85 g, m.p. 192°-193° C.

ANALYSIS: Calculated for C₂₃H₂₆FN₃O.C₄H₄O₄: 65.44% C; 6.10% H; 8.48% N;Found: 65.20% C; 6.19% H; 8.32% N

EXAMPLE 266N-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)-2-hydroxy-1-propyl]-1,2,3,4-tetrahydroquinolinehemifumarate

A stirred mixture ofN-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.41g, 8.73 mmol), 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol, inisopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solutionwas cooled and the solvent was removed on a rotary evaporator. The crudesolid was purified by flash chromatography over a silica gel column(SiO₂, 40 g, eluted with methylene chloride DCM, and 1-3% MeOH in DCM).The product thus purified weighed 2.0 g. This material was dissolved inethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq)in ethanol. The solids collected were recrystallized again from ethanol(50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p.170°-171° C.

ANALYSIS: Calculated for C₂₄H₂₈FN₃O₄.0.5.C₄H₄O₄: 66.79% C; 6.47% H;8.99% N; Found: 66.27% C; 6.54% H; 8.86% N

EXAMPLE 267N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetyl]-10,11-dihydro-5H-dibenz[b,f]azepinefumarate

A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine(6.6 g, 24.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g,22.7 mmol) and K₂CO₃ (3.5 g, 40 mmol) in acetonitrile (300 ml) washeated at reflux for 4 hours. The insolubles were filtered, and thesolvent was removed on a rotary evaporator. The crude product waspurified by flash chromatography over a silica gel column (100 g ofSiO₂; eluted with dichloromethane (DCM) and 1-2% C;H₃OH in DCM). Theproduct thus obtained weighed 8.7 g as a yellow oil. A sample (1.5 g) ofthis material was dissolved in ethanol and was treated with a solutionof fumaric acid in ethanol (360 mg/3 ml). The solids collected wererecrystallized from acetonitrile to yield 890 mg of white crystals, m.p.182°-183° C.

ANALYSIS: Calculated for C₂₈H₂₆FN₃O₂.C₄HO₄: 67.24% C; 5.29% H; 7.35% N;Found: 66.66% C; 5.17% H; 7.33% N

EXAMPLE 268N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl[ethoxyphthalimidehemihydrate

A mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (3.42 g, 15 mmol),N-(2-bromoethoxy)-phthalimide (4.3 g, 16 mmol) and K₂CO₃ (26 g, 18 mmol)in acetonitrile (150 ml) was heated at reflux for 2 hours. The solidswere removed and the solvent was evaporated. The residue was purifiedover a flash chromatography column (packed with SiO₂, 60 g; eluted withdichloromethane (DCM) and 1% C;H₃OH in DCM). The pure product thusobtained, weighing 6.8 g was crystallized from DCM:ethanol.Recrystallization from ethanol and i-propyl ether yielded white crystals(2.4 g, m.p. 125°-127° C.) as the hemihydrate.

ANALYSIS: Calculated for C₂₂H₂₀FN₃O₄.0.5.H₂O: 63.15% C; 5.05% H; 10.04%N; 2.15% H₂O Found: 63.20% C; 5.16% H; 9.80% N; 2.32% H₂O

EXAMPLE 2693-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl-2-hydroxy-1-propylaminehydrochloride hydrate

A stirred mixture of3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propylphthalimide(6.2 g, 14.6 mmol) and hydrazine hydrate (1.4 g, 28 mmol) in methanol(300 ml) was heated at reflux for 4 hours, then at 65 C. for 16 hours.The mixture was cooled and the solvent was stripped to dryness. Thewhite residue was stirred with H₂O (40 ml) and acidified with HCl topH=3. The milky white solids were filtered with the aid of Celite. Thelight yellow solution was basified with 50% NaOH to pH=9, then extractedwith methylene chloride (DCM, 3×180 ml). The DCM solution was washedwith brine, dried and stripped to give an oil (2.93 g) which solidifiedslowly. A 1 gm sample of this solid was treated with a HCl/MeOH solutionto precipitate out a hydrochloride salt. This salt was recrystallizedfrom ethanol=H₂O to yield 0.52 g of white crystals, m.p.=150°-152° C.

ANALYSIS: Calculated for C₁₅H₂₀FN_(O) ₂.HCl.H₂O: 51.80% C; 6.67% H;12.08% N; Found: 51.74% C; 6.32% H; 12.05% N

EXAMPLE 270N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-pyridinecarboxamidedihyydrochloride hydrate

To a mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (1.17 g,4.34 mmol) and triethylamine (1.08 g, 10.8 mmol) in chloroform (30 ml)was added nicotinoyl chloride hydrochloride (0.96 g, 5.4 mmol) in oneportion. The mixture was stirred for 1 hour at room temperature. Thesolution was diluted with methylene chloride (DCM) and washed with brineand dried over anhydrous MgSO₄. The solution was concentrated and thecrude product was purified by flash chromatography over a silica gelcolumn (SiO₂, 25 g; eluted with DCM and 1-3% MeOH in DCM). The free basethus purified weighed 1.7 g. This product was treated with 1M.HCl inethanol and recrystallized twice from methanol:isopropyl ether to yieldwhite crystals, 1.19 g, m.p. 243°-245° C. as a dihydrochloride hydrate.

ANALYSIS: Calculated for C₂₀H₂₁FN₄O₂.2HCl.H₂O: 52.30% C; 5.49% H; 12.20%N; 3.92% H₂O Found: 52.34% C; 5.39% H; 12.11% N; 3.68% H₂O

EXAMPLE 271N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-3-phenyl-2-quinoxalinaminedihydrochloride

A mixture of 2-[4-[(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethylamine(4.3 g, 16.3 mmol) and 2-chloro-3-phenylquinoxaline (4.7 g, 19.5 mmol)was heated at 160° C. for 5 hours in an autoclave. After standing atambient temperature for 2 days, the residue was partitioned betweenCH₂Cl₂ and H₂O. The CH₂Cl₂ extract was washed with H₂O, dried with MgSO₄and concentrated to yield 7.5 g of a brown solid. The solid was purifiedby preparative HPLC (Water's Associates Prep LC System 500, using 2silica gel columns and 4.5% MeOH—CH₂Cl₂ as eluent). Concentration oflater fractions afforded 2.3 g of the desired product as a yellow foam.A 1.4 g sample was suspended in MeOH (30 ml) and Et₂O—HCl (6.0 ml of a1.0 m Et₂O—HCl solution) was added. Initially a yellow solution formedand about 20 minutes later a precipitate began to form. The suspensionwas stirred for 30 minutes longer and anhydrous Et₂O (100 ml) was added.The resultant light yellow solid was collected to give 1.5 g. Theproduct was stirred in boiling CH₃CN (100 ml) for 1.0 hour and aftercooling the solid was isolated by filtration to afford 1.2 g of a lightyellow solid, m.p. 244°-246° C.

ANALYSIS: Calculated for C₂₇H₂₆FN₇.2HCl: 60.00% C; 5.22% H; 18.14% H;Found: 59.79% C; 5.27% H; 18.34% N

EXAMPLE 2721,2-bis-14-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethanedifumarate

To a stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine(2.2 g, 10 mmol) and K₂CO₃ (1.47 g, 11 mmol) in acetonitrile (50 ml) wasadded 1,2-dibromoethane (1 g, 5.4 mmol) dropwise at room temperature.The mixture was stirred at room temperature for 16 hours. The reactionmixture was filtered and the solvent was removed on a rotary evaporator.The crude solid was purified by flash chromatography (SiO₂, 30 g; elutedwith methylene chloride, DCM, and MeOH in DCM). The product thuspurified, weighed 513 mg. This solid was treated with fumaric acid (270mg, 2 eq) in ethanol. The crystals collected were recrystallized fromethanol:H₂O to yield 630 mg of white crystals, m.p.=246°-247° C.

ANALYSIS: Calculated for C₂₆H₂₈F₂N₄O₂: 58.45% C; 5.19% H; 8.02% N;Found: 58.36% C; 5.22% H; 7.92% N

EXAMPLE 2731,3-Bis-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxypropanedihydrochloride

A stirred mixture of1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (1.19g, 4.3 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (0.95 g,4.3 mmol) in isopropyl alcohol (50 ml) was heated at reflux for 1 hour,then stirred at 65° C. for 16 hours. The solvent was removed on a rotaryevaporator. The solid residues were purified by flash chromatographyover a silica gel column (SiO₂, 35 g; eluted with methylene chloride,DCM, and CH₃OH in DCM). The product thus obtained, weighed 2.55 g. Thismaterial was dissolved in ethanol and was treated with a solution of HCl(1M in ether). The salt collected weighed 2.35 g, m.p.>270° dec.

ANALYSIS: Calculated for C₂₇H₃₀F₂N₄O₃.2HCl: 56.95% C; 5.66% H; 9.84% N;Found: 56.55% C; 5.68% H; 9.51% N

EXAMPLE 2742-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)1-piperidinyl]ethyl]-2-phenyl-1,3-indandione

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.2 g, 10mmol), K₂CO₃ (1.6 g, 11.6 mmol) and2-toluenesulfonyl-2-phenyl-1,3-indandione (4.2 g, 10 mmol) inacetonitrile (50 ml) was heated at reflux for 3 hours. The mixture wascooled and the insolubles were filtered. The solvent was removed on arotary evaporator. The residue was purified twice using a flashchromatography column (SiO₂, 45 g and 40 g; eluted with DCM). Theproduct thus purified was recrystallized from ethanol (30 ml) andisopropyl ether, yield: 2.8 g, m.p. 149°-150° C.

ANALYSIS: Calculated for C₂₉H₂₅FN₂O₃: 74.34% C; 5.38% H; 5.98% N; Found:74.24% C; 5.50% H; 5.87% N

EXAMPLE 2752-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetonitrile

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50mmol), K₂CO₃ (8.5 g, 61.6 mmol) and 2-chloroacetonitrile (5.5 g, 73mmol) in acetonitrile (250 ml) was heated at reflux for 24 hours. Theinsolubles were filtered off and rinsed with methylene chloride (DCM).During concentration of the solvents on the rotary evaporator, crystalsappeared. The crystals were collected and weighed 5.79 g. The product inthe mother liquor was further purified by flash chromatography over asilica gel column (SiO₂, 70 g; eluted with DCM, and 1% C;H₃OH in DCM).The second crop of product thus obtained weighed 5.2 g. The total yieldwas 10.9 g. The sample was recrystallized once more form ethanol, m.p.130°-132° C.

ANALYSIS: Calculated for C₁₄H₁₄FN₃O: 64.85% C; 5.44% H; 16.21% N; Found:64.68% C; 5.32% H; 16.26% N

EXAMPLE 2763-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionitrile

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50mmol), K₂CO₃ (8.5 g, 74 mmol) and 3-bromopropionitrile (8.2 g, 1.2 eq)in acetonitrile (300 ml) was heated at reflux for 24 hours. The mixturewas cooled and the insolubles were filtered. The solvent was removed ona rotary evaporator and the crude product was purified by flashchromatography over a silica gel column (SiO₂, 120 g). The product thuspurified weighed 8.94 g. Recrystallization from ethanol yielded thenitrile as white crystals 4.3 g, m.p. 100°-100° C.

ANALYSIS: Calculated for C₁₅H₁₆FN₃O: 65.92% C; 5.90% H; 15.37% N; Found:65.87% C; 5.87% H; 15.37% N

EXAMPLE 2771-Phenoxycarbonyl-3-(1-phenoxycarbonyl-4-piperidinyl)-1H-indazole

To a suspension of 3-(1-methyl-4-piperidinyl)-1H-indazole (5.0 g, 23.2mmol) in DCM (100 ml) was added potassium carbonate (8.0 g, 58.0 mmol)followed by the dropwise addition of phenyl chloroformate (6.9 ml, 51.0mmol) at room temperature. After stirring for five days, the reactionwas filtered through a pad of celite and the solids were washed withDCM. The combined filtrates were concentrated and the remaining solidwas purified via flash column chromatography (silica gel, 10%methanol/DCM) to give 6.7 g of the1-phenoxycarbonyl-3-(1-methyl-4-piperidinyl)-1H-indazole as thehydrochloride salt. The free amine of the latter compound was preparedin Na₂CO₃ (sat.) and extracted into EtOAc. Concentration of the organiclayer afforded 4.7 g of the free amine which was used without furtherpurification.

To a solution of1-phenoxycarbonyl-3-(1-methyl-4-piperidinyl)-1H-indazole) (4.7 g, 14.0mmol) in DCM (100 ml) was added potassium carbonate (0.85 g, 6.2 mmol)followed by phenyl chloroformate (2.1 ml, 15.4 mmol) at roomtemperature, under nitrogen. After stirring for 2 days, the reactionmixture was filtered through a pad of celite and the solids were washedwith DCM. The remaining oil was purified via flash column chromatography(silica gel, DCM) to give another oil which solidified from EtOAc/pet.ether. The white solid (4.2 g) was collected via filtration and washedwith pet ether, m.p. 113°-116° C.

ANALYSIS: Calculated for C₂₆H₂₃N₃O₄: 70.74% C; 5.25% H; 9.52% N; Found:70.47% C; 5.17% H; 9.38% N

EXAMPLE 278 [4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]acetonitrile

A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (6.0 g, 2.7 mmol),NaHCO₃ (2.5 g, 3.0 mmol) chloroacetonitrile (2.5 g, 3.3 mmol) and CH₃CN(150 mol) was stirred at reflux under N₂ for 18 hours. The cooledreaction was poured into H₂O and the aqueous solution was extracted withEtOAc. The EtOAc extract was washed with H₂O, washed with brine, driedwith MgSO₄ and concentrated to yield 7.0 g of a tan solid. A 1.3 gsample was recrystallized from EtOAc to yield 0.65 g of a beige solid,m.p. 154°-156° C.

ANALYSIS: Calculated for C₁₃H₁₄FN₅: 60.22% C; 5.44% H; 27.01% N; Found:59.97% C; 5.55% H; 26.91% N

EXAMPLE 279 1-[4-(3-Chloropropoxy)-3-methoxyphenyl-2-hydroxyethanone

A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g,17.7 mmol), [bis(trifluoroacetoxy)iodolbenzene (15.6 g, 36.2 mmol), H₂O(18 ml), CF₃CO₂H (2.8 ml) and CH₃ CN (90 ml) was refluxed for 3 hours.The CH₃CN was removed under reduced pressure and the resulting yellowliquid was partitioned between H₂O and CH₂Cl₂. The biphasic mixture wasfiltered, the organic phase collected, washed with saturated NaHCO₃solution and concentrated to afford 1.5 g of an amorphous brown solid.The solid was flash chromatographed on silica gel, eluting the columnwith 5% EtOAc/CH₂Cl₂. Concentration of similar fractions afforded 0.7 gof the compound as a pale yellow solid, m.p. 99°-101° C.

EXAMPLE 2801-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone

A mixture of 3-(4-piperidinyl)-6-fluoro-1,2-benzisoxazole (1.3 g, 5.8mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2-hydroxyethanone (1.5 g,5.8 mmol), NaHCO₃ (1.5 g) and 1-methyl-2-pyrrolidinone (50 ml) wasstirred under N₂ at 100° C. for 6 hours. The reaction was poured intoH₂O, and the aqueous suspension was extracted with EtOAc. The extractwas washed (H₂O), dried (MgSO₄) and concentrated to afford the product.

This invention thus provides a group of chemical compounds that arecapable of producing antipsychotic effects and may be capable ofaffecting negative symptoms of schizophrenia in a beneficial manner. Inaddition, many of the compounds may also have reduced tendencies toproduce extrapyramidal side effects in mammals.

We claim:
 1. A compound of the formula:

wherein, X is —O—, —S—, —NH—, or —N(R₂)—; R₂ is selected from the groupconsisting of lower alkyl, aryl lower alkyl, aryl, (C₃-C₁₀)cycloalkyl,aroyl, (C₂-C₁₈)alkanoyl, (C₁-C₁₈)alkoxycarbonyl, and phenylsulfonylgroups; aryl is as defined hereinafter; p is 1 or 2; Y is hydrogen,lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy,trifluoromethyl, nitro, or amino; A is —C(═O)—, —C(═S)—, —C(═CH₂)—,—C(═O)CH₂—, —CH₂CH₂—, —CR₂₆═N—, or —CR₂₅R₁₆—; R₂₅ is hydrogen,(C₁-C₆)alkyl, hydroxy, or (C₁-C₈)alkanoyloxy; R₂₆ is hydrogen or(C₁-C₆)alkyl; either one of B_(y) and B_(z) is CH or N and the other isCH; U is O or S; q is 1, 2, 3, or 4; R₁ is—CR₂₄R₂₇-(CR₂₃R₂₄)_(n)—CR₂₄R₂₇— where n is 0, 1, 2, or 3; or—CHR₂₄—CH═CH—CHR₂₄—, —CHR₂₄—C≡C—CHR₂₄—, —CHR₂₄—CH═CH—CR₂₃R₂₄—CHR₂₄—,—CHR₂₄—CR₂₃R₂₄—CH═CH—CHR₂₄—, —CHR₂₄—C≡C—CR₂₃R₂₄—CHR₂₄—, or—CHR₂₄—CR₂₃R₂₄—C≡C—CHR₂₄—, the —CH═CH— bond being cis or trans; R₂₃ ishydrogen, (C₁-C₁₈) linear alkyl, phenyl, hydroxy, (C₁-C₁₈)alkoxy,aryloxy, aryl(C₁-C₁₈)alkyloxy, (C₁-C₁₈)alkanoyloxy, hydroxy(C₁-C₆)alkyl,(C₁-C₁₈)alkoxy(C₁-C₆)alkyl, phenyl(C₁-C₆)alkoxy,aryl(C₁-C₁₈)alkyloxy(C₁-C₆)alkyl, (C₁-C₁₈)alkanoyloxy(C₁-C₆)alkyl, or

where Z₁ is lower alkyl, —OH, lower alkoxy, —CF₃, —NO₂, —NH₂ or halogen,and p is as previously defined, and wherein aryl is as definedhereinafter; and R₂₄ is hydrogen, (C₁-C₁₈)linear alkyl, phenyl,hydroxy(C₁-C₆)alkyl, (C₁-C₁₈)alkoxy(C₁-C₆)alkyl, phenyl(C₁-C₆)alkyloxy,aryl(C₁-C₁₈)alkyloxy(C₁-C₆)alkyl, (C₁-C₁₈)alkanoyloxy(C₁-C₆)alkyl, or

where Z₁ is as previously defined, and p is as previously defined; R₂₇is hydrogen or R₂₄ and R₂₇ taken together with the carbon to which theyare attached form C═O or C═S; and R₄ is hydrogen, lower alkyl, loweralkoxy, hydroxy, tri(C₁-C₆)alkylsilyloxy, hydroxy lower alkyl,alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C₁-C₁₈)acylamino, (C₁-C₁₈)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine,—O—C(═O)—(C₁-C₁₈ straight or branched chain)alkyl or —C(═O)-aryl; inwhich aryl is phenyl or

wherein R₅ is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine,fluorine, bromine, iodine, lower monoalkylamino, lower dialkylaminedialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy; withthe proviso that R ₂₃ is not hydrogen, (C ₁ -C ₁₈)linear alkyl, phenyl,or

when R ₂₇ is hydrogen and R ₂₄ is hydrogen, (C ₁ -C ₁₈)linear alkyl,phenyl, or

with the proviso that R ₂₄ is not hydrogen, (C ₁ -C ₁₈)linear alkyl,phenyl, or

when R ₂₇ is hydrogen and n is 0; or when R ₂₇ is hydrogen and R ₂₃ ishydrogen, (C ₁ -C ₁₈)linear alkyl, phenyl, or

or when R ₁ is —CHR ₂₄ —CH═CH—CHR ₂₄ — or —CHR ₂₄ —C≡C—CHR ₂₄ —; and,any hydroxyl group attached to an aliphatic or aromatic carbon atom, orany primary or secondary nitrogen atom may be acylated with a(C₄-C₁₈)carboxylic (C ₄ -C ₁₈)alkanoyl group, ; in addition, anynitrogen atom may alternatively be acylated with a(C₄-C₁₈)alkoxycarbonyl group; and q is 1, 2, 3, or 4; all geometric,optical, and stereoisomers thereof, or a pharmaceutically acceptableacid addition salt thereof.
 2. An antipsychotic composition, whichcomprises the compound of claim 1 in an amount sufficient to produce anantipsychotic effect, and a pharmaceutically acceptable carrier.
 3. Amethod of treating psychoses, which comprises administering to a mammala psychoses-treating amount of the compound of claim
 1. 4. An analgesiccomposition, which comprises the compound of claim 1 in an amountsufficient to produce a pain-relieving effect, and a pharmaceuticallyacceptable carrier.
 5. A method of alleviating pain, which comprisesadministering to a mammal a pain-relieving effective amount of thecompound of claim
 1. 6. A depot pharmaceutical composition, whichcomprises a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of the compound of claim 1, wherein the compoundcontains an acylated hydroxy group, or an acylated amino group.
 7. Thedepot pharmaceutical composition of claim 6, wherein the hydroxy groupis acylated with a (C ₄ -C ₁₈)alkanoyl group, or the amino group isacylated with a (C₄-C₁₈)alkanoyl group or a (C₄-C₁₈)alkoxycarbonylgroup.
 8. The composition of claim 6, which contains a pharmaceuticallyacceptable oil.
 9. The composition of claim 8, wherein the oil isselected from the group consisting of coconut oil, peanut oil, sesameoil, cottonseed oil, corn oil, soybean oil, olive oil, and esters offatty acids and polyfunctional alcohols.
 10. The composition of claim 7,which contains a pharmaceutically acceptable oil.
 11. The composition ofclaim 10, wherein the oil is selected from the group consisting ofcoconut oil, peanut oil, sesame oil, cottonseed oil, corn oil, soybeanoil, olive oil, and esters of fatty acids and polyfunctional alcohols.12. A method for providing a long acting antipsychotic effect, whichcomprises injecting into a mammal an amount of the composition of claim6 sufficient to produce a long acting antipsychotic effect.
 13. A methodfor providing a long acting antipsychotic effect, which comprisesinjecting into a mammal an amount of the composition of claim 7sufficient to produce a long acting antipsychotic effect.
 14. A methodfor providing a long acting antipsychotic effect, which comprisesinjecting into a mammal an amount of the composition of claim 11sufficient to produce a long acting antipsychotic effect.
 15. A compoundof the formula:

wherein X is —O—, —S—, —NH—, or —N(R ₂)—; R ₂ is selected from the groupconsisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl,alkanoyl, and phenylsulfonyl groups, wherein aryl is as definedhereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine,fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, oramino, when p is 1; Y is lower alkoxy, hydroxy or halogen, when p is 2and X is —O—; q is 1, 2, 3, or 4; in which (R ₁) is R ₂₀ , R ₂₁ or R ₂₂, wherein: R ₂₀ is —(CH ₂)_(n) —, where n is 2, 3, 4 or 5; R ₂₁ is —CH ₂—CH═CH—CH ₂ —, —CH ₂ —CH≡C—CH ₂ —, —CH ₂ —CH═CH—CH ₂ —CH ₂ —, —CH ₂ —CH₂ —CH═CH—CH ₂ —, —CH ₂ —CH≡C—CH ₂ —CH ₂ —, or —CH ₂ —CH ₂ —C≡C—CH ₂ —,the —CH═CH— bond being cis or trans; R ₂₂ is R ₂₀ or R ₂₁ in which oneor more carbon atoms of R ₂₀ or R ₂₁ are substituted by at least one C ₁-C ₆ linear alkyl group, phenyl group or

where Z ₁ is lower alkyl, —OH, lower alkoxy, —CF ₃ , —NO ₂ , —NH ₂ orhalogen, and p is as previously defined; and R ₄ is hydrogen, loweralkyl, lower alkoxy, hydroxy, amino, mono- or dialkylamino, C ₁ -C ₃acyl amino, C ₁ -C ₆ alkanoyl, trifluoromethyl, chlorine, fluorine,bromine, —O—C(═O)—(C ₁ -C ₁₂ straight or branched chain) alkyl or—C(═O)-aryl; in which aryl is phenyl or

where R ₅ is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine,fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino,nitro, cyano, trifluoromethyl, or trifluoromethoxy; all geometric,optical, and stereoisomers thereof, or a pharmaceutically acceptableacid addition salt thereof.
 16. A pharmaceutical composition whichcomprises a compound of claim 15 and a pharmaceutically acceptablecarrier therefor.
 17. An antipsychotic composition, which comprises thecompound of claim 15 in an amount sufficient to produce an antipsychoticeffect, and a pharmaceutically acceptable carrier.
 18. A method oftreating psychoses, which comprises administering to a mammal apsychoses-treating amount of the compound of claim
 15. 19. An analgesiccomposition, which comprises the compound of claim 15 in an amountsufficient to produce a pain-relieving effect, and a pharmaceuticallyacceptable carrier.
 20. A method of alleviating pain, which comprisesadministering to a mammal a pain-relieving effective amount of thecompound of claim
 15. 21. A depot pharmaceutical composition, whichcomprises a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of the formula:

wherein X is —O—, —S—, —NH—, or —N(R ₂)—; R ₂ is selected from the groupconsisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl,alkanoyl, alkoxycarbonyl, and phenylsulfonyl groups, wherein aryl is asdefined hereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy,chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl,nitro, or amino, when p is 1; Y is lower alkoxy, hydroxy or halogen,when p is 2 and X is —O—; q is 1, 2, 3, or 4; in which (R ₁) is R ₂₀ , R₂₁ or R ₂₂ , wherein: R ₂₀ is —(CH ₂)_(n) —, where n is 2, 3, 4 or 5; R₂₁ is —CH ₂ —CH═CH—CH ₂ —, —CH ₂ —CH≡C—CH ₂ —, —CH ₂ —CH═CH—CH ₂ —CH ₂—, —CH ₂ —CH ₂ —CH═CH—CH ₂ —, —CH ₂ —CH≡C—CH ₂ —CH ₂ —, or —CH ₂ —CH ₂—C≡C—CH ₂ —, the —CH═CH— bond being cis or trans; R ₂₂ is R ₂₀ or R ₂₁in which one or more carbon atoms of R ₂₀ or R ₂₁ are substituted by atleast one C ₁ -C ₆ linear alkyl group, phenyl group or

where Z ₁ is lower alkyl, —OH, lower alkoxy, —CF ₃ , —NO ₂ , —NH ₂ orhalogen, and p is as previously defined; and R ₄ is hydrogen, loweralkyl, lower alkoxy, hydroxy, amino, mono- or dialkylamino, C ₁ -C ₃acyl amino, C ₁ -C ₆ alkanoyl, trifluoromethyl, chlorine, fluorine,bromine, —O—C(═O)—(C ₁ -C ₁₂ straight or branched chain) alkyl or—C(═O)-aryl; in which aryl is phenyl or

where R ₅ is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine,fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino,nitro, cyano, trifluoromethyl, or trifluoromethoxy; and, any hydroxylgroup attached to an aliphatic or aromatic carbon atom, or any primaryor secondary nitrogen atom may be acylated with a (C ₄ -C ₁₈)alkanoylgroup; in addition, any nitrogen atom may alternatively be acylated witha (C ₄ -C ₁₈)alkoxycarbonyl group; all geometric, optical, andstereoisomers thereof, or a pharmaceutically acceptable acid additionsalt thereof.
 22. The composition of claim 21, which contains apharmaceutically acceptable oil.
 23. The composition of claim 22,wherein the oil is selected from the group consisting of coconut oil,peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, oliveoil, and esters of fatty acids and polyfunctional alcohols.
 24. Thedepot pharmaceutical composition of claim 21, wherein the hydroxy groupis acylated with a (C ₄ -C ₁₈)alkanoyl group, or the amino group isacylated with a (C ₄ -C ₁₈)alkanoyl group or a (C ₄ -C ₁₈)alkoxycarbonylgroup.
 25. The composition of claim 24, which contains apharmaceutically acceptable oil.
 26. The composition of claim 25,wherein the oil is selected from the group consisting of coconut oil,peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, oliveoil, and esters of fatty acids and polyfunctional alcohols.
 27. A methodfor providing a long acting antipsychotic effect, which comprisesinjecting into a mammal an amount of the composition of claim 21sufficient to produce a long acting antipsychotic effect.
 28. A methodfor providing a long acting antipsychotic effect, which comprisesinjecting into a mammal an amount of the composition of claim 23sufficient to produce a long acting antipsychotic effect.
 29. A methodfor providing a long acting antipsychotic effect, which comprisesinjecting into a mammal an amount of the composition of claim 26sufficient to produce a long acting antipsychotic effect.
 30. A compoundof the formula:

wherein X is —O—, —S—, —NH—, or —N(R ₂)—; R ₂ is selected from the groupconsisting of lower alkyl, aryl lower alkyl, aryl, (C ₃ -C₁₀)cycloalkyl, aroyl, (C ₂ -C ₁₈)alkanoyl, (C ₁ -C ₁₈)alkoxycarbonyl,and phenylsulfonyl groups; aryl is as defined hereinafter; p is 2; Y islower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy,trifluoromethoxy, nitro or amino when X is —S—, —NH—, or —N(R ₂)—; Y islower alkyl, trifluoromethoxy, nitro or amino when X is —O—; A is—C(═O)—, —C(═S)—, —C(═CH ₂)—, —C(═O)CH ₂ —, —CH ₂ CH ₂ —, —CR ₂₆ ═N—, or—CR ₂₅ R ₂₆ —; R ₂₅ is hydrogen, (C ₁ -C ₆)alkyl, hydroxy, or (C ₁ -C₈)alkanoyloxy; R ₂₆ is hydrogen or (C ₁ -C ₆)alkyl; either one of B _(y)and B _(z) is CH or N and the other is CH; U is O or S; q is 1, 2, 3, or4; R ₁ is —CR ₂₄ R ₂₇—(CR ₂₃ R ₂₄)_(n) —CR ₂₄ R ₂₇ —, where n is 0, 1,2, or 3; or —CHR ₂₄ —CH═CH—CHR ₂₄ —, —CHR ₂₄ —C≡C—CHR ₂₄ —, —CHR ₂₄—CH═CH—CR ₂₃ R ₂₄ —CHR ₂₄ —, —CHR ₂₄ —CR ₂₃ R ₂₄ —CH═CH—CHR ₂₄ —, —CHR₂₄ —C≡C—CR ₂₃ R ₂₄ —CHR ₂₄ , or —CHR ₂₄ —CR ₂₃ R ₂₄ —C≡C—CHR ₂₄ —, the—CH═CH— bond being cis or trans; R ₂₃ is hydrogen, (C ₁ -C ₁₈)linearalkyl, phenyl, hydroxy, (C ₁ -C ₁₈)alkoxy, aryloxy, aryl(C ₁ -C₁₈)alkyloxy, (C ₁ -C ₁₈)alkanoyloxy, hydroxy(C ₁ -C ₆)alkyl, (C ₁ -C₁₈)alkoxy(C ₁ -C ₆)alkyl, aryl(C ₁ -C ₁₈)alkyloxy(C ₁ -C ₆)alkyl, (C ₁-C ₁₈)alkanoyloxy(C ₁ -C ₆)alkyl, or

where Z ₁ is lower alkyl, —OH, lower alkoxy, —CF ₃ , —NO ₂ , —NH ₂ , orhalogen, and p is as previously defined, and wherein aryl is as definedhereinafter; and R ₂₄ is hydrogen, (C ₁ -C ₁₈)linear alkyl, phenyl,hydroxy(C ₁ -C ₆)alkyl, (C ₁ -C ₁₈)alkoxy(C ₁ -C ₆)alkyl, phenyl(C ₁ -C₆)alkyloxy, aryl(C ₁ -C ₁₈)alkyloxy(C ₁ -C ₆)alkyl, (C ₁ -C₁₈)alkanoyloxy(C ₁ -C ₆)alkyl, or

where Z ₁ is as previously defined, and p is as previously defined; R ₂₇is hydrogen or R ₂₄ and R ₂₇ taken together with the carbon to whichthey are attached form C═O or C═S; and R ₄ is hydrogen, lower alkyl,lower alkoxy, hydroxy, tri(C ₁ -C ₆)alkylsilyloxy, hydroxy lower alkyl,alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C ₁ -C ₁₈)acylamino, (C ₁ -C ₁₈)alkanoyl, trifluoromethyl, chlorine, fluorine,bromine, —O—C(═O)—(C ₁ -C ₁₈ straight or branched chain)alkyl or—C(═O)-aryl; in which aryl is phenyl or

wherein R ₅ is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine,fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino,nitro, cyano, trifluoromethyl, or trifluoromethoxy; any hydroxyl groupattached to an aliphatic or aromatic carbon atom, or any primary orsecondary nitrogen atom may be acylated with a (C ₄ -C ₁₈)alkanoylgroup; in addition, any nitrogen atom may alternatively be acylated witha (C ₄ -C ₁₈)alkoxycarbonyl group; all geometric, optical, andstereoisomers thereof; or a pharmaceutically acceptable acid additionsalt thereof.
 31. An antipsychotic composition, which comprises thecompound of claim 30 in an amount sufficient to produce an antipsychoticeffect, and a pharmaceutically acceptable carrier.
 32. A method oftreating psychoses, which comprises administering to a mammal apsychoses-treating amount of the compound of claim
 30. 33. An analgesiccomposition, which comprises the compound of claim 30 in an amountsufficient to produce a pain-relieving effect, and a pharmaceuticallyacceptable carrier.
 34. A method of alleviating pain, which comprisesadministering to a mammal a pain-relieving effective amount of thecompound of claim
 30. 35. A depot pharmaceutical composition, whichcomprises a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of the compound of claim 30, wherein the compoundcontains an acylated hydroxy group, or an acylated amino group.
 36. Thedepot pharmaceutical composition of claim 35, wherein the hydroxy goupis acylated with a (C ₄ -C ₁₈)alkanoyl group, or the amino group isacylated with a (C ₄ -C ₁₈)alkanoyl group of a (C ₄ -C ₁₈)alkoxycarbongroup.
 37. The composition of claim 35, which contains apharmaceutically acceptable oil.
 38. The composition of claim 37,wherein the oil is selected from the group consisting of coconut oil,peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, oliveoil, and esters of fatty acids and polyfunctional alcohols.
 39. Thecomposition of claim 36, which contains a pharmaceutically acceptableoil.
 40. The composition of claim 39, wherein the oil is selected fromthe group consisting of coconut oil, peanut oil, sesame oil, cottonseedoil, corn oil, soybean oil, olive oil, and esters of fatty acids andpolyfunctional alcohols.
 41. A method for providing a long actingantipsychotic effect, which comprises injecting into a mammal an amountof the composition of claim 36 sufficient to produce a long actingantipsychotic effect.
 42. A method for providing a long actingantipsychotic effect, which comprises injecting into a mammal an amountof the composition of claim 38 sufficient to produce a long actingantipsychotic effect.
 43. A method for providing a long actingantipsychotic effect, which comprises injecting into a mammal an amountof the composition of claim 40 sufficient to produce a long actingantipsychotic effect.